Compositions, synthesis, and methods of using phenylcycloalkylmethylamine derivatives

ABSTRACT

The present invention provides novel phenylcycloalkylmethylamine derivatives, and methods of preparing phenylcycloalkylmethylamine derivatives. The present invention also provides methods of using phenylcycloalkylmethylamine derivatives and compositions of phenylcycloalkylmethylamine derivatives. The pharmaceutical compositions of the compounds of the present invention can be used for treating and/or preventing obesity and obesity related co-morbid indications and depression and depression related co-morbid indications.

This application is a Continuation of U.S. patent application Ser. No.13/731,670, filed Dec. 31, 2012, now U.S. Pat. No. 9,238,625; whichclaims priority to U.S. Provisional Application No. 61/582,201, filedDec. 30, 2011; the contents of the above identified applications areincorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention relates to phenylcycloalkylmethylaminederivatives, synthesis of phenylcycloalkylmethylamine derivatives andmethods of using phenylcycloalkylmethylamine derivatives for thepharmacological treatment of obesity, depression and obesity relatedco-morbid indications.

BACKGROUND

Obesity is a chronic disease that affects millions of people across theworld especially in the developed countries. It is defined by excessbody fat and is generally measured by calculating a person's BMI (bodymass index). If a person's BMI is 30 or above, he or she considered tobe obese. Obesity can cause a number of health problems either directlyor indirectly, such as, for example, type 2 diabetes, coronary heartdisease, high blood triglycerides, high blood pressure and stroke.Obesity also raises risk of certain types of cancer. Obese men are morelikely than normal-weight peers to die from cancer of the colon, rectum,and prostate. Obese women are more likely than non-obese women to diefrom cancer of the gallbladder, breast, uterus, cervix and ovaries.Death from some cancers may be more likely because obesity makes thecancers harder to detect in the early stages (for example, the initialsmall lump of breast cancer may not be felt in an obese woman). Recentstudies show obesity increases the risk of Alzheimer's-type dementia.Other disease and health problems linked to obesity include: gallbladderdisease, gallstones, osteoarthritis, gout or joint pain, sleep apnea,psychological and social problems.

Obesity is caused by multiple factors, the primary factor being geneticswhich is the one factor relating to obesity over which individuals haveno control. Other important factors involved in obesity are: themechanisms of fat storage; the balance between energy intake and energyexpenditure; an individual's life style: eating habits and exercise; andpsychological, cultural and socioeconomic influences. Despite theseeming inexorable progression of this disease, there have been limitedadvances in the pharmacotherapy of this condition. Drugs to treatobesity can be divided into three groups: those that reduce food intakeor appetite suppressants; those that alter metabolism or block theabsorption of fat; and those that increase thermogenesis. Currently,there are only two drugs approved by the FDA for the long-term treatmentof obesity and they are fat absorption blocker orlistat (XENICAL®) andthe appetite suppressant sibutramine (MERIDIA®). The only thermogenicdrug combination that has been tested is ephedrine and caffeine, butthis treatment has not been approved by regulatory agencies.

The fat absorption blocker, orlistat works in the gastrointestinal tractby blocking an enzyme that is needed to digest fat. Instead of beingabsorbed from the intestine, up to one-third of the fat that a personconsumes is excreted in the stool. In addition, orlistat blocks theabsorption of needed fat-soluble vitamins A, D, E, and K, as well asbeta-carotene. This is one of the major limitations of this drug for thelong term use in the treatment of obesity. Most commonly reported otherside effects of orlistat are bloating, diarrhea and oily stools.

In the appetite suppressant category, a few noradrenergic andserotonergic drugs belong to a family of 2-arylmethylamines arecurrently available in the market for the treatment of obesity. Thenoradrenergic agents such as phenylpropanolamine, (ACUTRIM®, DEXATRIM®),diethylpropion (TENUATE®), and phentermine (FASTIN®, IONAMIN®) areapproved for the short-term treatment of obesity. Whereas, noradrenergicand serotonergic agent sibutramine (MERIDIA®) is the only drug currentlyapproved for the long-term treatment of obesity in the appetitesuppressant category. Sibutramine has cyclobutanemethylamine backboneand it is this backbone mainly responsible for its uniquepharmacological properties.

In the last 10 years, a number of reports have been published on thepossible use of sibutramine, either alone or in combination with othertherapeutic agents, for the treatment and/or prevention of a varietydiseases and/or disorders in addition to obesity (see, Montana, J. G.,WO 2004/058237; Lulla, A. et al., WO 2004/096202; Jerussi, T. P. et al.,WO 02/060424; Senanayake, C. H. et al., WO 01/51453; Heal, D. J., WO01/00205; Birch, A. M. et al., WO 01/00187; Mueller, P., WO 00/32178;Bailey, C., WO 98/11884; Kelly, P., WO 98/13034). For examples:treatment of nausea, emesis, and related conditions; cognitivedysfunctions; eating disorders; weight gain; irritable bowel syndrome;obsessive compulsive disorders; platelet adhesion; apnea, affectivedisorders such as attention deficit disorders, depression, and anxiety;male and female sexual function disorders; restless leg syndrome;osteoarthritis; substance abuse including nicotine and cocaineaddiction; narcolepsy; pain such as neuropathic pain, diabeticneuropathy, and chronic pain; migraines; cerebral function disorders;chronic disorders such as premenstrual syndrome; and incontinence.

In general, sibutramine has a number of therapeutic benefits because ofits unique pharmacological properties. However, sibutramine'stherapeutic use for the treatment of obesity, and other diseases anddisorders is currently not fully utilized because of certain limitationsand adverse side effects associated with the drug. The major adverseevents reported, in some cases life threatening, include increase inblood pressure and the side effects derived from the drug-druginteractions, for example, serotonin syndrome. The majority of theseadverse events are, to some extent, metabolism-based. Sibutramine exertsits pharmacological actions predominantly via its secondary (M₁) andprimary (M₂) amine metabolites. Sibutramine is metabolized in the liverprincipally by the cytochrome P450 (3A4) isozymes, to desmethylmetabolites, M₁ and M₂. These active metabolites are further metabolizedby hydroxylation and conjugation to pharmacologically inactivemetabolites, M₅ and M₆. The elimination half-lives of therapeuticallyactive primary and secondary metabolites M₁ and M₂ are 14 and 16 hours,respectively. It is evident from a number literature reports thatcytochrome P450 mediated metabolism and the long half lives of activemetabolites (M₁ and M₂) are to a great extent responsible for adverseevents such as increased blood pressure and other side effects derivedfrom drug-drug interactions of sibutramine.

Therefore, there is a need and great demand for safer and effective nextgeneration appetite suppressants for the treatment of obesity. An idealdrug in this class should have potent appetite suppressant activity, aproven effect on fat loss, be well tolerated during acute and chronicadministration and have alleviated side effects when compared tosibutramine and phentermine.

SUMMARY OF THE INVENTION

The present invention is directed towards compositions of novelphenylcycloalkylmethylamine derivatives and the use of the compositionsfor the treatment of obesity, and related co-morbid conditions anddepression and related co-morbid conditions. The present inventionprovides methods for synthesizing such phenylcycloalkylmethylaminederivatives. The present invention also provides methods for usingphenylcycloalkylmethylamine derivatives and pharmaceutical compositionof phenylcycloalkylmethylamine derivatives for treating or preventingobesity and co-morbid diseases and/or disorders and for treating orpreventing depression and co-morbid diseases and/or disorders.

The compounds of the present disclosure are advantageous because oftheir favorable metabolic, pharmacokinetics and pharmacologicalprofiles.

The present invention provides phenylcycloalkylmethylamine derivativesof structural Formula (I):

or isomer or pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, 4, or 5;

SP is a spacer, wherein the spacer is C₁₋₆ alkylene, and wherein one ormore of the carbons of the C₁₋₆ alkylene is optionally substituted withO, S, or NR⁶, wherein R⁶ is H or C₁₋₆ alkyl;

X is O, S, NR⁶ or S(O)(O);

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, C₁₋₆ alkyl,aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl,heteroarylalkyl, acylalkyloxycarbonyl, acyloxyalkyloxycarbonyl,acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, C₁₋₆ alkoxy,alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylamino,alkylsulfinyl, alkyl sulfonyl, alkylthio, amino, alkylamino,arylalkylamino, dialkylamino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy,aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate,sulfate, sulfonate, or sulfonamide; optionally R¹, R², R³, R⁴, and R⁵ issubstituted with the isotopes ²H (deuterium), ³H (tritium), ¹³C, ¹⁵N,¹⁷O, ¹⁸O, ¹⁸F, ³¹P, ³²P, ³⁵S, and ³⁶Cl; and

“*” denotes a carbon capable of being optically active.

The compounds of the present disclosure include (R)-isomers,(S)-isomers, and mixtures of (R)- and (S)-isomers.

DETAILED DESCRIPTION

This invention provides compounds, pharmaceutical compositions andmethods for pharmacological treatment of obesity and related co-morbiddiseases and/or disorders. This invention also provides methods forsynthesis of novel appetite suppressants.

DEFINITIONS

The compounds of the invention may contain one or more chiral centersand/or double bonds and therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereoisomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedcompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds of theinvention may also exist in several tautomeric forms including the enolform, the keto form and mixtures thereof. Accordingly, the chemicalstructures depicted herein encompass all possible tautomeric forms ofthe illustrated compounds. The compounds of the invention also includeisotopically labeled compounds where one or more atoms have an atomicmass different from the atomic mass of conventionally found in nature.Examples of isotopes that may be incorporated into the compounds of theinvention include, but are not limited to ²H, ³H, ¹³C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.

“Alkyl” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl(allyl), cycloprop-1-en-1yl, cycloprop-2-en-1yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc. The term “C₁₋₆ alkyl”encompasses C₁ alkyl, C₂ alkyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆alkyl.

The term “alkyl” specifically intended to include radicals having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkany,”“alkenyl,” and “alkynyl,” are used. Preferably, an alkyl group comprisesfrom 1-20 carbon atoms, more preferably, from 1 to 10 carbon atoms.

The term “alkylene” refers to the removal of a hydrogen atom from“alkanyl.”

“Alkanyl” refers to a saturated branched, straight-chain or cyclic alkylradical derived by the removal of one hydrogen atom from a single carbonatom of a parent alkane. Typical alkanyl groups include but are notlimited to, methanyl; ethanyl; propanyls such as propan-1-yl,propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such asbutan-1-yl, butan-2-yl(sec-butyl), 2-methyl-propan-1-yl(isobutyl),2-methyl-propan-2-yl(t-butyl), cyclobutan-1-yl, etc.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicalkyl radical having at least one carbon-carbon double bond derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkene. The group may be in either the cis or trans conformation aboutthe double bond(s). Typical alkenyl groups include, but are not limitedto, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl,cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methy-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien 1-yl, etc.

“Alkylene” refers to a divalent radical that is a branched or unbranchedhydrocarbon fragment containing the specified number of carbon atoms,and having two points of attachment. Alkylenes are optionallysubstituted with one, two or three substituents. The term “C₁₋₆alkylene” encompasses C₁ alkylene, C₂ alkylene, C₃ alkylene, C₄alkylene, C₅ alkylene, C₆ alkylene, and any sub-range thereof. Examplesof alkylenes include without limitation: methylene (—CH₂—, a C₁alkylene), ethylene (—CH₂CH₂—, a C₂ alkylene), propylene (—CH₂CH₂CH₂—, aC₃ alkylene), and butylene (—CH₂CH₂CH₂CH₂—, a C₄ alkylene).

“Alkynyl” refers to an unsaturated branched, straight-chain or cyclicalkyl radical having at least one carbon-carbon triple bond derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such asbut-1-yn-1-yl, but-1-yn3-yl, but-3-yn-1-yl, etc.

“Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl.

“Acyloxyalkyloxycarbonyl” refers to a radical —C(O)OCR′R″OC(O)R′″, whereR′, R″, and R′″ are each independently hydrogen, alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but not limited to —C(O)OCH₂OC(O)CH₃, —C(O)OCH₂OC(O)CH₂CH₃,—C(O)OCH(CH₃)OC(O)CH₂CH₃, —C(O)OCH(CH₃)OC(O)C₆H₅.

“Acylalkyloxycarbonyl” refers to a radical —C(O)OCR′R″C(O)R′″, where R′,R″, and R″ are each independently hydrogen, alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but not limited to —C(O)OCH₂C(O)CH₃, —C(O)OCH₂C(O)CH₂CH₃,—C(O)OCH(CH₃)C(O)CH₂CH₃, —C(O)OCH(CH₃)C(O)C₆H₅.

“Acyloxyalkyloxycarbonylamino” refers to a radical—NRC(O)OCR′R″OC(O)R′″, where R, R′, R″, and R′″ are each independentlyhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl,heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein that may beoptionally substituted by one or more substituents as defined herein.Representative examples include, but not limited to —NHC(O)OCH₂OC(O)CH₃,—NHC(O)OCH₂OC(O)CH₂CH₃, —NHC(O)OCH(CH₃)OC(O)CH₂CH₃,—NHC(O)OCH(CH₃)OC(O)C₆H₅.

“Acylalkyloxycarbonylamino” refers to a radical —NRC(O)OCR′R″C(O)R′″,where R, R′, R″, and R′″ are each independently hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but not limited to —NHC(O)OCH₂C(O)CH₃, —NHC(O)OCH₂C(O)CH₂CH₃,—NHC(O)OCH(CH₃)C(O)CH₂CH₃, —NHC(O)OCH(CH₃)C(O)C₆H₅.

“Alkylamino” means a radical —NHR where R represents an alkyl, orcycloalkyl group as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to, methylamino, ethylamino,1-methylethylamino, cyclohexylamino.

“Alkoxy” refers to a radical —OR where R represents an alkyl, orcycloalkyl group as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to methoxy, ethoxy, propoxy, butoxy,cyclohexyloxy.

“Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy is asdefined herein.

“Alkoxycarbonylalkoxy” refers to a radical —OCR′R″C(O)-alkoxy wherealkoxy is as defined herein. Similarly, where R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to—OCH₂C(O)OCH₃, —OCH₂C(O)OCH₂CH₃, —OCH(CH₃)C(O)OCH₂CH₃,—OCH(C₆H₅)C(O)OCH₂CH₃, —OCH(CH₂C₆H₅)C(O)OCH₂CH₃,—OC(CH₃)(CH₃)C(O)OCH₂CH₃.

“Alkoxycarbonylalkylamino” refers to a radical —NRCR′R″C(O)-alkoxy wherealkoxy is as defined herein. Similarly, where R, R′, R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to—NHCH₂C(O)OCH₃, —N(CH₃)CH₂C(O)OCH₂CH₃, —NHCH(CH₃)C(O)OCH₂CH₃,—NHCH(C₆H₅)C(O)OCH₂CH₃, —NHCH(CH₂C₆H₅)C(O)OCH₂CH₃, and—NHC(CH₃)(CH₃)C(O)OCH₂CH₃.

“Alkylsulfonyl” refers to a radical —S(O)₂R where R is an alkyl, orcycloalkyl group as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, and butyl sulfonyl.

“Alkylsulfinyl” refers to a radical —S(O)R where R is an alkyl, orcycloalkyl group as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to, methylsulfinyl, ethylsulfinyl,propylsulfinyl, and butylsulfinyl.

“Alkylthio” refers to a radical —SR where R is an alkyl or cycloalkylgroup as defined herein that may be optionally substituted by one ormore substituents as defined herein. Representative examples include,but are not limited to methylthio, ethylthio, propylthio, and butylthio.

“Aryl” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorine, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleidene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene. Preferable, an aryl groupcomprises from 6 to 20 carbon atoms, more preferably, between 6 to 12carbon atoms.

“Arylalkyl” refers to an acyclic alkyl in which one of the hydrogenatoms bonded to a carbon atom, typically a terminal or sp³ carbon atom,is replaced with an aryl group. Typically arylalkyl groups include, butnot limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl,naphthobenzyl, 2-naphthophenylethan-1-yl. Where specific alkyl moietiesare intended, the nomenclature arylalkany, arylalkenyl and/orarylalkynyl is used. Preferably, an arylalkyl group is(C₆-C₃₀)arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C₁-C₁₀) and the aryl moiety is (C₆-C₂₀), morepreferably, an arylalkyl group is (C₆-C₂₀) arylalkyl, e.g., the alkanyl,alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₈) and the arylmoiety is (C₆-C₁₂).

“Arylalkoxy” refers to an —O-arylalkyl radical where arylalkyl is asdefined herein that may be optionally substituted by one or moresubstituents as defined herein.

“Arylalkoxycarbonylalkoxy” refers to a radical —OCR′R″C(O)-arylalkoxywhere arylalkoxy is as defined herein. Similarly, where R′ and R″ areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to—OCH₂C(O)OCH₂C₆H₅, —OCH(CH₃)C(O)OCH₂C₆H₅, —OCH(C₆H₅)C(O)OCH₂C₆H₅,—OCH(CH₂C₆H₅)C(O)OCH₂C₆H₅, —OC(CH₃)(CH₃)C(O)OCH₂C₆H₅.

“Arylalkoxycarbonylalkylamino” refers to a radical—NRCR′R″C(O)-arylalkoxy where arylalkoxy is as defined herein.Similarly, where R, R′, R′ and R″ are each independently hydrogen,alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,heteroaryl, heteroarylalkyl, as defined herein that may be optionallysubstituted by one or more substituents as defined herein.Representative examples include, but are not limited to—NHCH₂C(O)OCH₂C₆H₅, —N(CH₃)CH₂C(O)OCH₂C₆H₅, —NHCH(CH₃)C(O)OCH₂C₆H₅,—NHCH(C₆H₅)C(O)OCH₂C₆H₅, —NHCH(CH₂C₆H₅)C(O)OCH₂C₆H₅,—NHC(CH₃)(CH₃)C(O)OCH₂C₆H₅.

“Aryloxycarbonyl” refers to radical —C(O)—O-aryl where aryl is definedherein that may be optionally substituted by one or more substituents asdefined herein.

“Aryloxycarbonylalkoxy” refers to a radical —OCR′R″C(O)-aryloxy wherearyloxy is as defined herein. Similarly, where R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to—OCH₂C(O)OC₆H₅, —OCH(CH₃)C(O)OC₆H₅, —OCH(C₆H₅)C(O)OC₆H₅,—OCH(CH₂C₆H₅)C(O)OC₆H₅, —OC(CH₃)(CH₃)C(O)OC₆H₅.

“Aryloxycarbonylalkylamino” refers to a radical —NRCR′R″C(O)-aryloxywhere aryloxy is as defined herein. Similarly, where R, R′, R′ and R″are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl,aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as definedherein that may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to—NHCH₂C(O)OC₆H₅, —N(CH₃)CH₂C(O)OC₆H₅, —NHCH(CH₃)C(O)OC₆H₅,—NHCH(C₆H₅)C(O)OC₆H₅, —NHCH(CH₂C₆H₅)C(O)OC₆H₅, —NHC(CH₃)(CH₃)C(O)OC₆H₅.

“Carbamoyl” refers to the radical —C(O)NRR where each R group isindependently, hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein.

“Carbamate” refers to a radical —NR′C(O)OR″, where R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to,methylcarbamate (—NHC(O)OCH₃), ethylcarbamate (—NHC(O)OCH₂CH₃),benzylcarbamate (—NHC(O)OCH₂C₆H₅).

“Carbonate” refers to a radical —OC(O)OR, where R is alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to, methyl carbonate (—C(O)OCH₃),cyclohexyl carbonate (—C(O)OC₆H₁₁), phenyl carbonate (—C(O)OC₆H₅),benzyl carbonate (—C(O)OCH₂C₆H₅).

“Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl or cycloalkyl group as defined herein that may beoptionally substituted by one or more substituents as defined herein.Representative examples include, but are not limited to dimethylamino,methylethylamino, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino,(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino.

“Halo” means fluoro, chloro, bromo, or iodo.

“Heteroaryl” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene. Preferably, the heteroaryl group isbetween 5-20 membered heteroaryl, with 5-10 membered heteroaryl beingparticularly preferred. Preferred heteroaryl groups are those derivedfrom thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,quinoline, imidazole, oxazole and pyrazine.

“Heteroaryloxycarbonyl” refers to a radical —C(O) OR where R isheteroaryl as defined that may be optionally substituted by one or moresubstituents as defined herein.

“Heteroarylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with a heteroaryl group. Preferably, theheteroarylalkyl radical is a 6-30 carbon membered heteroarylalkyl, e.g.,the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10membered and the heteroaryl moiety is a 5-20 membered heteroaryl, morepreferably, a 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenylor alkynyl moiety of the heteroarylalkyl is 1-8 membered and theheteroaryl moiety is a 5-12 membered heteroaryl.

“Isomer” refers to compounds of the present invention that possessasymmetric carbon atoms (optical centers) or double bonds, theracemates, diastereomers, enantiomers, geometric isomers, structuralisomers and individual isomers are all intended to be encompassed withinthe scope of the present invention.

As used herein, the term “patient” encompasses mammal patients. Examplesof mammals include, but are not limited to, any member of the mammalianclass: humans, non-human primates such as chimpanzees, and other apesand monkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention, which is pharmaceutically acceptable and possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, or formed with organic acids such as acetic acid,propionic acid, hexanoic acid, cyclopentane propionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2,2,2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid; or (2) salts formedwhen an acidic proton present in the parent compound is replaced by ametal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base such as ethanolamine,diethanolamine, triethanolamine, or N-methylglucamine.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

“Phosphate” refers to a radical —OP(O)(OR′)(OR″), where R′ and R″ areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein.

“Phosphonate” refers to a radical —P(O)(OR′)(OR″), where R′ and R″ areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein.

“Preventing” or “Prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Protecting group” refers to a group of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in Green et al., “ProtectiveGroups in Organic Chemistry”, (Wiley, 2^(nd) ed. 1991) and Harrison etal., “Compendium of Synthetic Organic Methods”, vols. 1-8 (John Wileyand Sons, 1971-1996). Representative amino protecting groups include,but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl,benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethyl silyl(“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityl and substitutedtrityl groups, allyloxycarbonyl, 9-fluorenylmethyloxy-carbonyl (“FMOC”),nitroveratryloxycarbonyl (“NVOC”). Representative hydroxyl protectinggroups include, but are not limited to, those where the hydroxyl groupis either acylated or alkylated such as benzyl, and trialkylsilyl ethersand allyl ethers.

“Racemate” refers to an equimolar mixture of enantiomers of a chiralmolecule.

“Spacer” refers to a C₁₋₆ alkylene in which one or more of the carbonsof the C₁₋₆ alkylene can optionally be replaced with O, S, or NR⁶,wherein R⁶ can be H or C₁₋₆ alkyl. The C₁₋₆ alkylene is optionallysubstituted. In certain aspects, the C₁₋₆ alkylene is optionallysubstituted by acylalkyloxycarbonyl, acyloxyalkyloxycarbonyl,acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, alkoxy,alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonyllalkylamino,alkylsulfinyl, alkyl sulfonyl, alkylthio, amino, alkylamino,arylalkylamino, dialkylamino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy,aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate,sulfate, sulfonate, or sulfonamide.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituents(s).Typical substituents include, but are not limited to, —X, —R⁵⁴, —O⁻, ═O,—OR⁵⁴, —SR⁵⁴, —S, ═S, —NR⁵⁴R⁵⁵, ═NR⁵⁴, —CX₃, —CF₃, —CN, —OCN, —SCN, —NO,—NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂OR⁵⁴, —OS(O)₂O³¹, —OS(O)₂R⁵⁴,—P(O)(O—)₂, —P(O)(OR¹⁴)(O³¹), —OP(O)(OR⁵⁴)(OR⁵⁵), —C(O)R⁵⁴, —C(S)R⁵⁴,—C(O)OR⁵⁴, —C(O)NR⁵⁴R⁵⁵, —C(O)O⁻, —C(S)OR⁵⁴, —NR⁵⁶C(O)NR⁵⁴R⁵⁵,—NR⁵⁶C(S)NR⁵⁴R⁵⁵, —NR⁵⁷C(NR⁵⁶)NR⁵⁴R⁵⁵, and —C(NR⁵⁶)NR⁵⁴R⁵⁵, where each Xis independently a halogen; each R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ are independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl.

“Sulfate” refers to a radical —OS(O)(O)OR, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein.

“Sulfonamide” refers to a radical —S(O)(O)NR′R″, where R′ and R″ areindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein or optionally R′ and R″ together with the atom to whichthey are both attached form a cycloheteroalkyl or substitutedcycloheteroalkyl ring. Representative examples include but not limitedto azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,4-(NR′″)-piperazinyl or imidazolyl group wherein said group may beoptionally substituted by one or more substituents as defined herein.R′″ is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl,heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein that may beoptionally substituted by one or more substituents as defined herein.

“Sulfonate” refers to a radical —S(O)(O)OR, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein.

“Thio” means the radical —SH.

“Treating” or “Treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the patient. In yet another embodiment, “treating” or“treatment” refers to inhibiting the disease or disorder, eitherphysically (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and itsseverity and the age, weight, etc., of the patient to be treated, andcan be determined by one of skill in the art without undueexperimentation.

Compounds of the Invention

The present invention provides phenylcycloalkylmethylamine derivativesof Formula (I):

or isomer or pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, 4, or 5; preferably n is 0 (cyclopropyl), 1(cyclobutyl), 2 (cyclopentyl), or 3 (cyclohexyl), and more preferably nis 1.

SP is a spacer, wherein the spacer is C₁₋₆ alkylene, and wherein one ormore of the carbons of the C₁₋₆ alkylene is optionally substituted withO, S, or NR⁶, wherein R⁶ is H or C₁₋₆ alkyl;

X is O, S, NR⁶ or S(O)(O);

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, C₁₋₆ alkyl,aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl,heteroarylalkyl, acylalkyloxycarbonyl, acyloxyalkyloxycarbonyl,acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, C₁₋₆ alkoxy,alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkylamino,alkylsulfinyl, alkyl sulfonyl, alkylthio, amino, alkylamino,arylalkylamino, dialkylamino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, aryloxycarbonylalkoxy,aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate,sulfate, sulfonate, or sulfonamide; optionally R¹, R², R³, R⁴, and R⁵ issubstituted with the isotopes ²H (deuterium), ³H (tritium), ¹³C, ¹⁵N,¹⁷O, ¹⁸O, ¹⁸F, ³¹P, ³²P, ³⁵S, and ³⁶Cl; and

“*” denotes a carbon capable of being optically active.

The compounds of the present invention include (R)-isomers, (S)-isomers,and mixtures of (R)- and (S)-isomers. In one embodiment, the compoundsare optically pure (R)-isomers, as they often are more active. Inanother embodiment, the compounds are optically pure (S)-isomers. Yet inanother embodiment, the compounds are racemic compounds.

In one preferred embodiment, le and R² are independently H, C₁₋₆ alkoxy(e.g., methoxy, ethoxy), halo (e.g., fluoro, chloro), or hydroxyl.

In one preferred embodiment, R³ is H or C₁₋₆ alkyl (e.g., isobutyl).

In one preferred embodiment, R⁴ is H.

In one preferred embodiment, SP is C₁₋₆alkylene.

In one preferred embodiment, R⁵ is C₁₋₆ alkyl.

In one preferred embodiment, R⁶ is C₁₋₆ alkyl.

The compounds of this invention described herein can have one or more ofthe following characteristics or properties:

-   -   1. Compounds of the invention can have dopamine transporter        (DAT), norepinephrine transporter (NET) and serotonin        transporter (SERT) inhibitory properties;    -   2. Oral bioavailability of the compounds is consistent with oral        administration using standard pharmacological oral formulations;        however, the compounds, and compositions thereof, can also be        administered using any delivery system that produces constant        and controllable blood levels over time.

In some embodiments, the subject invention provides compounds having anytwo or more of the above identified characteristics or properties. In apreferred embodiment the compounds of the invention have all fourcharacteristics or properties.

Additional modifications of the compounds disclosed herein can readilybe made by those skilled in the art. Thus, analogs and salts of theexemplified compounds are within the scope of the subject invention.With knowledge of the compounds of the subject invention skilledchemists can use known procedures to synthesize these compounds fromavailable substrates. As used in this application, the term“derivatives” refers to compounds which are substantially the same asanother compound but which may have been modified by, for example,adding additional side groups. The term “derivatives” as used in thisapplication also may refer to compounds which are substantially the sameas another compound but which have atomic or molecular substitution atcertain locations in the compound.

The subject invention further pertains to enantiomerically isolatedcompounds, and compositions comprising the compounds. The isolatedenantiomeric forms of the compounds of the invention are substantiallyfree from one another (i.e., in enantiomeric excess). In other words,the “R” forms of the compounds are substantially free from the “S” formsof the compounds and are, thus, in enantiomeric excess of the “S” forms.Conversely, “S” forms of the compounds are substantially free of “R”forms of the compounds and are, thus, in enantiomeric excess of the “R”forms. In one embodiment of the invention, the isolated enantiomericcompounds are at least about in 80% enantiomeric excess. In a preferredembodiment, the compounds are at least about in 90%, 95%, 97%, or 99%enantiomeric excess.

Synthesis of the Compounds of the Invention

The compounds of the invention can be obtained via the synthetic methodsillustrated in Schemes 1. Several methods have been described in the artfor the synthesis of cycloalkylmethylamine analogs (see, e.g. U.S. Pat.No. 5,596,019; WO 2004/096202; WO 02/083631; WO 02/36540; WO 02/060424;Jeffery, J. E. et al., J. Chem. Soc. Perkin Trans 1, 1996, 2583-2589.).Other methods are known in the art for synthesizingcycloalkylmethylamines, which are readily accessible to the skilledartisan. The starting materials and intermediates used in the synthesisof target molecules (Scheme 1-8) thereof are commercially available orcan be prepared by established procedures (See e.g., Green et al.,“Protective Groups in Organic Synthesis,” (Wiley, 4^(rd) ed., 2006);Harrison et al “Compendium of Synthetic Organic Methods,” vols. 1-8(John Wiley and Sons, 1971-1996); “Beilstein Handbook of OrganicChemistry, Frankfurt, Germany; Feiser et al, “Reagents for OrganicSynthesis,” Volumes 1-45, Karger, 1991; March, Advanced OrganicChemistry,” Wiley Interscience, 4^(th) ed., 1992; Larock “ComprehensiveOrganic Transformations,” Wiley-VCH Publishers, 2^(nd) ed., 1999;Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John Wileyand Sons, 1^(st) ed., 1995).

Accordingly, starting materials useful for preparing compounds of theinvention and intermediates thereof are commercially available or can beprepared by well-known synthetic methods. Other methods for thesynthesis of cycloalkylmethylamines described herein are eitherdescribed in the art or will be readily apparent to the skilled artisanin view of the references provided above and may be used to synthesizethe compounds of the invention. Accordingly, the methods presented inthe Schemes herein are illustrative rather than comprehensive.

Methods

In one method, phenylcycloalkylmethylamine derivatives (7, 8) of Formula(I) are prepared as described in Scheme 2. The startingphenylcycloalkylamine building blocks (6) are prepared by modifying areported procedure by Jeffery et al. (J. Chem. Soc., Perkin Trans. 1,1996, 2583-2589) as illustrated in Scheme 1. The typical procedureinvolves reaction of a cycloalkylnitrile (3) with an appropriateGrignard reagent (R³MgBr) in presence of toluene at a gentle refluxtemperature for 10 to 24 hours followed by treating the intermediatewith sodium borohydride in methanol or ethanol to get the correspondingcycloalkylmethylamine (6). The cycloalkylnitriles (3) used in thepreparation of cycloalkylamines (6) are either purchased fromSigma-Aldrich or synthesized from the corresponding phenylacetonitriles(1) using standard chemistries. The selected racemic amines (6) areseparated into corresponding optically pure (R)- and (S)-isomers by astandard chiral crystallization method using optically pure tartaricacid.

The phenylcycloalkylmethylamines (6) are alkylated with appropriate4-nitrophenylsulfonyl esters (9) using cesium carbonate inN,N-dimethylformamide (DMF) solvent at room temperature to get thecorresponding cycloalkylmethylamine ether derivatives (7, 8) in moderateto good yields as illustrated in scheme 2. The building blocks,4-nitrophenylsulfonyl esters (9) are synthesized as illustrated inscheme 6.

In another method, the phenylcycloalkylmethylamine ether derivatives (7,8) are prepared by coupling with appropriate alkoxyalkylcarboxylic acids(10) followed by reduction of the amide intermediates (11) with lithiumaluminum hydride (LAH) in anhydrous THF in moderate yields asillustrated in Scheme 2. The alkoxyalkylcarboxylic acids (10) areprepared as illustrated in scheme 7.

In another method, phenylcycloalkylmethylamine derivatives (12, 13) ofFormula (I) are prepared as described in Scheme 3. Thephenylcycloalkylamines (6) are coupled with appropriatealkylthioalkylcarboxylic acids (14) to get the amides (15) which afterreduction with lithium aluminum hydride give the correspondingphenylcycloalkylmethylamine thioether derivatives (12, 13). Thealkylthioalkylcarboxylic acids (14) are synthesized as illustrated inScheme 8.

In another method phenylcycloalkylmethylamine derivatives (17) ofFormula (I) are prepared as described in Scheme 4. Thephenylcycloalkylamines (15) are oxidized using m-chloroperbenzoic acid(mCPBA) to get the amides (16) which after reduction with lithiumaluminum hydride give the corresponding phenylcycloalkylmethylaminederivatives (17).

In another method, phenylcycloalkylmethylamine derivatives (19) ofFormula (I) are prepared as described in Scheme 5. Thephenylcycloalkylamines (6) are coupled with appropriatealkylaminoalkylcarboxylic acid esters (20) in presence oftrimethylaluminum in toluene to get the amides (21) which afterreduction with borane-dimethylsulfide (BH₃-DMS) solution in toluene orLAH in THF give the corresponding phenylcycloalkylmethylaminederivatives (19).

The optically pure (R)- and (S)-phenylcycloalkylmethylamine derivativeshaving Formula I are either prepared from the corresponding opticallypure amines (6) or by subjecting the corresponding racemicphenylcycloalkylmethylamine derivatives (7, 8, 12, 13, 17 and 19) usingchiral HPLC separation techniques. All phenylcycloalkylmethylaminederivatives (7, 8, 12, 13, 17 and 19) are converted into correspondinghydrochloride salts by treating with 2N HCl solution in ether understandard conditions.

The building blocks p-nitrophenylsulfonyl protected ethers (9) used inthe synthesis of phenylcycloalkylmethylamine derivatives are synthesizedin four steps as illustrated in scheme 6. The mono-benzyl protecteddiols (24) are synthesized by benzylating the corresponding diols (23)using sodium hydride as base in anhydrous tetrahydrofuran (THF) at 0° C.followed by refluxing the reaction mixture in good yields. The benzylprotected alcohols (24) are alkylated with appropriate alkyl halideusing sodium hydride as base in anhydrous N,N-dimethylformamide (DMF) toget the ethers (25). The benzyl protecting group is cleaved understandard hydrogenation conditions to give the corresponding alcohol (26)which are reacted with p-nitrophenylsulfonylchloride using the mild basetriethylamine in dichloromethane solvent to get thep-nitrophenylsulfonyl protected ethers (9) in overall good yields.

The starting building blocks 4-alkoxyalkylcarboxylic acid (10) issynthesized in two steps as illustrated in scheme 7. Thegamma-butyrolactone (28) is reacted with ethylorthoformate (29) in thepresence of ethanol and sulfuric acid to get the corresponding4-ethoxybutyric acid ester (30) in good yields. The saponification ofester (30) under standard reaction conditions give the corresponding4-ethoxybutyric acid (10) in good yield.

The starting building blocks alkylthioalkylcarboxylic acids (14) aresynthesized in two steps as illustrated in scheme 8. The sodiumthiolates (32) are alkylated with bromoalkylcarboxylic acids (31) inanhydrous DMF to get the esters (33) which after saponification give thecorresponding alkylthioalkylcarboxylic acids (14).

Therapeutic Uses of Compounds of Formula (I)

In various aspects, the present disclosure provides methods of treatingor preventing obesity, depression, and associated co-morbid conditionsin a patient. The method comprises administering to a patient in need ofsuch treatment an effective amount of any one of the compounds ofstructural Formula (I). In further aspects, the method treats obesity,depression and related co-morbid symptom.

The present invention provides methods of treating and preventingobesity and associated co-morbid conditions. The term “co-morbidconditions associated with obesity” used in this document means medicalconditions known to those skilled in the art to be associated withobesity. The term includes but not limited to the following: diabetesincluding non-insulin dependent diabetes mellitus, impaired glucosetolerance, hypertension, coronary thrombosis, stroke, depression,anxiety, psychoses (for example schizophrenia), tardive dyskinesia, drugaddiction, drug abuse, cognitive disorders, Alzheimer's disease,cerebral ischaemia, obsessive-compulsive behavior, panic attacks, socialphobias, eating disorders such as bulimia, anorexia, snacking and bingeeating, lipid syndromes, hyperglycemia, hyperlipidemia, and stress inmammals particularly humans.

In addition, the compounds, compositions, and methods of the presentinvention can be used in the treatment or prevention of metabolicdiseases and conditions arising therefrom, or for example non exerciseactivity thermogenesis and increased metabolic rate, sexual dysfunction,sleep apnoea, premenstrual syndrome, urinary incontinence includingstress incontinence, hyperactivity disorders, hiatial hernia, and refluxesophagitis, pain, especially neuropathic pain, weight gain associatedwith drug treatment, chronic fatigue syndrome, osteoarthritis and gout,cancers associated with weight gain, menstrual dysfunction, gallstones,orthostatic hypotension and pulmonary hypertension.

The compounds, compositions, and methods of the present invention can beuseful in preventing cardiovascular disease, and in reducing plateletadhesiveness, in aiding weight loss after pregnancy, reducing thecraving to smoke and in aiding weight loss after smoking cessation. Thepresent invention can also be useful in lowering uric acid levels andlipid levels in mammals particularly humans.

In accordance with the invention, a compound and/or a compositioncontaining a compound of structural Formula (I) is administered to apatient, preferably a human, suffering from obesity and associated withco-morbid diseases and/or disorders. In certain embodiments, thecompounds and/or compositions of the invention are administered to apatient, preferably a human, as a preventive measure against variousdiseases or disorders. Thus, the compounds and/or compositionscontaining compound(s) of structural Formula (I) may be administered asa preventive measure to a patient having a predisposition for obesityand associated co-morbid diseases and/or disorders (see WO 2004/058237;WO 2004/096202; WO 02/060424; WO 01/51453; WO 01/00205; WO 01/00187;Mueller, P. International Application Publication No. WO 00/32178; WO98/11884; WO 98/13034).

Thus, those of skill in the art may readily assay and use the compoundsand/or compositions containing compound(s) of Formulae (I) to treatobesity and associated co-morbid diseases and/or disorders.

Therapeutic/Prophylactic Administration

The compounds and/or compositions of the invention can be administeredor applied singly, or in combination with other pharmaceutically activeagents, to a patient.

The present compounds and/or compositions of the invention arepreferably administered orally. The compounds and/or compositions of theinvention may also be administered by any other convenient route, forexample, by infusion or bolus injection, by absorption throughepithelial or mucocutaneous linings (e.g., oral mucosa, rectal andintestinal mucosa, etc.). Administration can be systemic or local.Various delivery systems are known, (e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, etc.) that can be used toadminister a compound and/or composition of the invention. Methods ofadministration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravabinal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes or skin.

In particularly, preferred embodiments, the compounds and/orcompositions of the invention can be delivered via sustained releasesystems, preferably oral sustained release systems. In one embodiment, apump may be used (see, Langer, supra; Sefton, 1987, CRC Crit. RefBiomed. Eng. 14:201; Saudek et al., 1989, N. Engl. J. Med. 321:574).

In another embodiment, polymeric materials can be used (see “MedicalApplications of Controlled Release,” Langer and Wise (eds.), Wiley, NewYork (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. MacromolChem. 23:61; see also Levy et al., 1985, Science 228:190; During et al.,1989, Ann. Neurol. 25:351; Howard et al, 1989, J. Neurosurg. 71:105). Ina preferred embodiment, polymeric materials are used for oral sustainedrelease delivery. Preferred polymers include sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (more preferredhydroxypropylmethylcellulose). Other preferred cellulose ethers havebeen described in the art (Bamba et al., Int. J. Pharm., 1979, 2, 307).

In another embodiment, enteric-coated preparations can be used for oralsustained release administration. Preferred coating materials includepolymers with a pH-dependent solubility (i.e., pH-controlled release),polymers with a slow or pH-dependent rate of swelling, dissolution orerosion (i.e., time controlled release), polymers that are degraded byenzymes (i.e., enzyme controlled release) and polymers that form firmlayers that are destroyed by an increase in pressure (i.e.,pressure-controlled release).

In still another embodiment, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.,2000, 26:695-708). In a preferred embodiment, OROS® osmotic deliverysystems (Alza Corporation, Mountain View, Calif.) are used for oralsustained release delivery devices (See for example, U.S. Pat. Nos.3,845,770 and 3,916,899).

In yet another embodiment, a controlled-release system can be placed inproximity of the target of the compounds and/or composition of theinvention, thus requiring only a fraction of the systemic dose (See,e.g., Goodson, in “Medical Applications of Controlled Release,” supra,vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussedin Langer, 1990, Science 249:1527-1533 may also be used.

The compounds, and/or compositions containing compound(s) of Formula (I)of the invention may be cleaved either chemically and/or enzymatically.One or more enzymes present in the stomach, intestinal lumen, intestinaltissue, blood, liver, brain or any other suitable tissue of a mammal mayenzymatically cleave the compounds and/or compositions of the invention.

Compositions of the Invention

In various aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of structural Formula(I), and a pharmaceutically acceptable vehicle.

When administered to a patient, the compounds of the invention andpharmaceutically acceptable vehicles are preferably sterile. Water is apreferred vehicle when the compound of the invention is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid vehicles, particularly forinjectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol, or pH buffering agents. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents may be used.

The pharmaceutical compositions may be manufactured by means ofconventional mixing, dissolving, granulating, and emulsifying,encapsulating, entrapping or lyophilizing process. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compounds of the inventioninto preparations which can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, and capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical vehicles have been described in the art (see Remington'sPharmaceutical Sciences, Philadelphia College of Pharmacy and Science,17^(th) Edition, 1985). Preferred compositions of the invention areformulated for oral delivery, particularly for oral sustained releaseadministration.

Compositions for oral delivery may be in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups or elixirs, for example. Orally administered compositions maycontain one or more optionally agents, for example, sweetening agentssuch as fructose, aspartame or saccharin; flavoring agents such aspeppermint, oil of wintergreen, or cherry coloring agents and preservingagents to provide a pharmaceutically palatable preparation. When intablet or pill form, the compositions may be coated to delaydisintegration and absorption in the gastrointestinal tract, therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds ofthe invention. In these later platforms, fluid from the environmentsurrounding the capsule is imbibed by the driving compound, which swellsto displace the agent or agent composition through an aperture. Thesedelivery platforms can provide an essentially zero order deliveryprofile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Such vehiclesare preferably of pharmaceutical grade.

For oral liquid preparations such as suspensions, elixirs and solutions,suitable carriers, excipients or diluents include water, saline,alkyleneglycols (e.g., propylene glycol), polyalkylene glycols (e.g.,polyethylene glycol), oils, alcohols, slightly acidic buffers between pH4 and pH 6 (e.g., acetate, citrate, ascorbate at between about 1 mM toabout 50 mM) etc. Additionally, flavoring agents, preservatives,coloring agents, and bile salts may be added.

Compositions for administration via other routes may also becontemplated. For buccal administration, the compositions may take theform of tablets, lozenges, etc. formulated in conventional manner.Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundof the invention with a pharmaceutically acceptable vehicle. Preferably,the pharmaceutically acceptable vehicle is a liquid such as alcohol,water, polyethylene glycol or a perfluorocarbon. Optionally, anothermaterial may be added to alter the aerosol properties of the solution orsuspension of compounds of the invention. Preferably, this material isliquid such as alcohol, glycol, polyglycol or fatty acid. Other methodsof formulating liquid drug solutions or suspension suitable for use inaerosol devices are known to those of skill in the art (see, e.g., U.S.Pat. Nos. 5,112,598 and 5,556,611). A compound of the invention may alsobe formulated in rectal or vaginal compositions such as suppositories orretention enemas, e.g., containing conventional suppository bases suchas cocoa, butter or other glycerides. In addition to the formulationsdescribed previously, a compound of the invention may also be formulatedas depot preparation. Such long acting formulations may be administeredby implantation (for example, subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, a compound of the inventionmay be formulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

When a compound of the invention is acidic, it may be included in any ofthe above-described formulations as the free acid, a pharmaceuticallyacceptable salt, a solvate or hydrate. Pharmaceutically acceptable saltssubstantially retain the activity of the free acid, may be prepared byreaction with bases and tend to be more soluble in aqueous and otherprotic solvents than the corresponding free acid form.

Methods of Use and Doses

The present invention provides methods of treating or preventing obesityin a patient, the method comprising administering to a patient in needof such treatment an effective amount of any one of the compounds ofstructural Formula (I).

The amount of a compound of the invention effective in the treatment ofa particular disorder or condition disclosed herein will depend on thenature of the disorder or condition, and can be determined by standardclinical techniques known in the art as previously described. Inaddition, in vitro or in vivo assays may optionally be employed to helpidentify optimal dosage ranges. The amount of a compound of theinvention administered is dependent on, among other factors, the subjectbeing treated, and the weight of the subject, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician. For example, the dosage may be delivered in apharmaceutical composition by a single administration, by multipleapplications or controlled release. In a preferred embodiment, thecompounds of the invention are delivered by oral sustained releaseadministration. Preferably, in this embodiment, the compounds of theinvention are administered twice per day (or preferably, once per day).Dosing may be repeated intermittently, may be provided alone or incombination with other drugs and may continue as long as required foreffective treatment of the disease state or disorder.

The compounds of structural Formula (I) may be administered in the range0.1-500 mg, preferably 1-100 mg per day, given in one or more doses, andmore preferably 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 35 mg, or 50 mg perday, and most preferably 25 mg.

The compounds of the invention are preferably assayed in vitro and invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. The compounds of the invention may also be demonstrated to beeffective and safe using animal model systems.

The therapeutically effective dose of a compound of the inventiondescribed herein will provide therapeutic benefit without causingsubstantial toxicity. Toxicity of compounds of the invention may bedetermined using standard pharmaceutical procedures and may be readilyascertained by the skilled artisan. The dose ratio between toxic andtherapeutic effect is the therapeutic index. The dosage of a compound ofthe inventions described herein is within a range of circulatingconcentrations that include an effective dose with little or notoxicity.

The invention is further defined by reference to the following examples,which describe in detail preparation of compounds and compositions ofthe invention and assays for using compounds and compositions of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the invention.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

-   -   CDI=1,1′-Carbonyldiimidazole    -   DCM=dichloromethane    -   DMAP=4-N,N-dimethylaminopyridine    -   DMF=N,N-dimethylformamide    -   h=hours    -   HATU=O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   LC/MS=liquid chromatography/mass spectroscopy    -   M=molar    -   MTBE=methyl tert-butyl ether    -   rt=room temperature    -   TEA=triethylamine    -   THF=tetrahydrofuran    -   TFA=trifluoroacetic acid        General Procedure for Synthesis of Phenylcycloalkylmethylamine 6        (Scheme 1)

To a stirred solution of Grignard reagent (2M solution in ether, 0 065mol) under nitrogen atmosphere was added drop wise a solution ofphenylcycloalkylcarbonitrile (3) (0.026 mol) in 50 mL of toluene at 0°C. Then the reaction mixture was slowly heated at 92° C. for 18 h. Theprogress of the reaction was monitored by thin layer chromatography(TLC). The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was diluted with 30 mLof anhydrous methanol and cooled down at 0° C., and NaBH₄ (2.5 g) wasadded slowly portion wise. The resulting mixture was stirred untilcomplete conversion of imine intermediate to the corresponding amine.After the reaction was completed, methanol was removed by evaporation.The residue was diluted with ethyl acetate, washed with saturated sodiumbicarbonate, dried over MgSO₄ and evaporated under reduce pressure togive corresponding phenylcyclobutylmethylamine (6) which was purified bycolumn chromatography on silica gel using a gradient of hexane and ethylacetate. The pure products 6a-m gave satisfactory 1H NMR and/or Massspectral data.

Example 1 3-Methyl-1-(1-(p-tolyl)cyclopropyl)butan-1-amine (6a)

Colorless oil (1.66 g, 61%). ¹HNMR (400 MHz, CDCl₃): δ 0.65-0.70 (m,3H); 0.77-0.80 (m, 1H); 0.85 (d, J=6.8 Hz, 6H); 0.98-1.11 (m, 2H);1.22-1.30 (m, 2H); 1.70-1.77 (m, 1H); 2.10-1.13 (m, 1H); 2.28 (s, 3H);7.09 (d, J=8.0 Hz, 2H); 7.20 (d, J=8.0 Hz, 2H). MS (ESI): m/z=218.20(M+H⁺).

Example 2 1-(1-(4-Chlorophenyl)cyclopropyl)-3-methylbutan-1-amine (6b)

Colorless oil (1.60 g, 60%). ¹HNMR (400 MHz, CDCl₃): δ 0.65-0.70 (m,3H); 0.77-0.80 (m, 1H); 0.85 (d, J=6.8 Hz, 6H); 0.87-1.01 (m, 1H);1.18-1.27 (m, 3H); 1.69-1.73 (m, 1H); 2.16 (d, J=10.4 Hz, 1H); 7.23-7.24(m, 4H). MS (ESI): m/z=238.20 (M+H⁺).

Example 3 1-(1-(4-Florophenyl)cyclobutyl)-3-methylbutan-1-amine (6c)

Colorless oil (2.2 g, 70%). ¹HNMR (400 MHz, CDCl₃): δ 0.58-0.65 (m, 1H);0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.15-1.21 (m, 1H);1.67-1.70 (m, 1H); 1.80-1.86 (m, 1H); 1.93-1.98 (m, 1H); 2.12-2.18 (m,1H); 2.28-2.37 (m, 3H); 2.97 (dd, J=2.0 Hz; 10.8 Hz, 1H); 6.93-7.08 (m,3H); 7.12-7.16 (m, 1H).

Example 4 1-(1-(4-Chlorophenyl)cyclobutyl)-3-methylbutan-1-amine (6d)

Colorless oil (4.7 g, 72%). ¹HNMR (400 MHz, CDCl₃): δ 0.84 (d, J=6.8 Hz,3H); 0.88 (d, J=6.8 Hz, 3H); 1.13-1.23 (m, 2H); 1.66-1.68 (m, 1H);1.79-1.84 (m, 1H); 1.90-1.96 (m, 1H); 2.15-2.16 (m, 1H); 2.25-2.33 (m,3H); 2.98 (d, J=10.8 Hz, 1H); 7.06 (dd, J=1.6; 8.4 Hz, 2H); 7.24 (dd,J=1.6; 8.4 Hz, 2H).

Example 5 1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutan-1-amine(6e)

Colorless oil (3.6 g, 70%). ¹HNMR (400 MHz, CDCl₃): δ 0.53-0.60 (m, 1H);0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.10-1.13 (m, 1H);1.63-1.67 (m, 1H); 1.77-1.83 (m, 1H); 1.91-1.97 (m, 1H); 2.12-2.16 (m,1H); 2.21-2.33 (m, 3H); 2.97 (d, J=10.8 Hz, 1H); 6.96 (dd, J=2.0 Hz; 8.4Hz, 1H); 7.19 (d, J=2 Hz; 1H); 7.32 (d, J=8.4 Hz, 1H).

Example 6 1-(1-(2,4-Dichlorophenyl)cyclobutyl)-3-methylbutan-1-amine(6f)

Colorless oil (1.5 g, 72%). ¹HNMR (400 MHz, CDCl₃): δ 0.84 (d, J=6.8 Hz,3H); 0.88 (d, J=6.8 Hz, 3H); 1.13-1.15 (m, 1H); 1.23-1.26 (m, 1H)1.71-1.81 (m, 2H); 1.92-2.03 (m, 1H); 2.35-2.43 (m, 4H); 3.24 (dd, J=2.0Hz; 10.8 Hz, 1H); 7.02 (d, J=8.4 Hz, 1H); 7.16 (dd, J=2 Hz; 8.4 Hz, 1H);7.29 (d, J=2.4 Hz, 1H).

Example 7 1-(1-(3,4-Dimethoxyphenyl)cyclobutyl)-3-methylbutan-1-amine(6g)

Colorless oil (3.6 g, 70%). ¹HNMR (400 MHz, CDCl₃): δ 0.53-0.60 (m, 1H);0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.10-1.13 (m, 1H);1.63-1.67 (m, 1H); 1.77-1.83 (m, 1H); 1.91-1.97 (m, 1H); 2.12-2.16 (m,1H); 2.21-2.33 (m, 3H); 2.97 (d, J=10.8 Hz, 1H); 3.87 (s, 6H); 6.77-6.82(m, 3H).

Example 8 1 1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutan-1-amine (6h)

Colorless oil (1.06 g, 72%). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.64 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.15-1.21 (m, 1H);1.40 (t J=6.8 Hz, 3H); 1.67-1.69 (m, 1H); 1.79-1.84 (m, 1H); 1.90-1.96(m, 1H); 2.14-2.16 (m, 1H); 2.27-2.36 (m, 3H); 2.98 (dd, J=2.0 Hz; 10.8Hz, 1H); 4.02 (q, J=6.8 Hz, 2H); 6.83 (d, J=8.4 Hz, 2H); 7.05 (dd, J=8.4Hz, 2H).

Example 9 3-Methyl-1-(1-(4-(methylthio)phenyl)cyclobutyl)butan-1-amine(6i)

Colorless oil (1.7 g, 34%). ¹HNMR (400 MHz, CDCl₃): δ 0.56-0.62 (m, 1H);0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.04-1.06 (sbroad, 2H);1.13-1.20 (m, 1H); 1.64-1.68 (m, 1H); 1.79-1.83 (m, 1H); 1.90-1.95 (m,1H); 2.11-2.17 (m, 1H); 2.26-2.37 (m, 3H); 2.46 (s, 3H); 2.96 (d, J=10.8Hz, 1H); 7.05 (d, J=8.4 Hz, 2H); 7.19 (d, J=8.4 Hz, 2H). MS (ESI):m/z=264.20 (M+H⁺).

Example 10 3-Methyl-1-(1-(p-tolyl)cyclopentyl)butan-1-amine (6j)

Colorless oil (1.46 g, 60%). ¹HNMR (400 MHz, CDCl₃): δ 0.68-0.78 (m,1H); 0.83 (d, J=6.8 Hz, 6H); 0.99 (sbroad, 2H); 1.20-1.24 (m, 1H);1.50-1.56 (m, 2H); 1.58-1.68 (m, 3H); 1.72-1.78 (m, 1H); 1.84-1.91 (m,1H); 2.02-2.08 (m, 2H); 2.28 (s, 3H); 2.73 (d, J=10.8 Hz, 1H); 7.09 (d,J=8.0 Hz, 2H); 7.20 (d, J=8.0 Hz, 2H). MS (ESI): m/z=246.20 (M+H⁺).

Example 11 1-(1-(4-Methoxyphenyl)cyclopentyl)-3-methylbutan-1-amine (6k)

Colorless oil (1.43 g, 55%). ¹HNMR (400 MHz, CDCl₃): δ 0.66-0.77 (m,2H); 0.81 (d, J=6.8 Hz, 6H); 0.97-1.02 (sbroad, 2H); 1.12-1.18 (m, 1H);1.48-1.55 (m, 1H); 1.58-1.68 (m, 3H); 1.71-1.77 (m, 1H); 1.82-1.89 (m,2H); 2.07-2.06 (m, 1H); 2.70 (d, J=10.8 Hz, 1H); 3.78 (s, 3H); 6.82 (d,J=8.8 Hz, 2H); 7.23 (d, J=8.8 Hz, 2H). MS (ESI): m/z=262.20 (M+H⁺).

Example 12 3-Methyl-1-(1-(p-tolyl)cyclohexyl)butan-1-amine (6l)

Colorless oil (1.46 g, 60%). ¹HNMR (400 MHz, CDCl₃): δ 0.63-0.76 (m,1H); 0.77 (d, J=6.8 Hz, 3H); 0.83 (d, J=6.8 Hz, 3H); 1.17-1.32 (m, 5H);1.37-1.66 (m, 6H); 2.24-2.36 (m, 4H); 2.52 (d, J=10.4 Hz, 1H); 7.09 (d,J=8.0 Hz, 2H); 7.20 (d, J=8.0 Hz, 2H). MS (ESI): m/z=260.20 (M+H⁺).

Example 13 1-(1-(4-Chlorophenyl)cyclohexyl)-3-methylbutan-1-amine (6m)

Colorless oil (0.8 g, 32%). ¹HNMR (400 MHz, CDCl₃): δ 0.60-0.66 (m, 1H);0.75 (d, J=6.8 Hz, 3H); 0.81 (d, J=6.8 Hz, 3H); 0.95-1.00 (sbroad, 2H);1.11-2.25 (m, 5H); 1.41-1.62 (m, 5H); 2.20-2.30 (m, 2H); 2.53 (d, J=10.8Hz, 1H); 7.22 (d, J=8.8 Hz, 2H); 7.27 (d, J=8.8 Hz, 2H). MS (ESI):m/z=280.20 (M+H⁺).

General Procedure for Synthesis of Phenylcyclobutylmethylamine EtherDerivatives 7 and 8 (Scheme 2)

To a stirred solution of cesium carbonate (1.4 g, 5.0 eq) in 10 mL ofDMF was added appropriate phenylcyclobutylmethylamine (6) (0.0009 mol)and the resulting mixture was stirred at room temperature for 4 hrs.Then a solution suitable 4-nitrobenzenesulfonate (0.0045 mol. 5 eq) in 5mL of DMF was added over a period of 5 minutes. The resulting mixturewas stirred at rt temperature for overnight. The progress of thereaction was monitored by thin layer chromatography (TLC). The reactionmixture was filtered, diluted with 10 mL of ethyl acetate, washed withbrine and dried over Na₂SO₄, evaporated to give the correspondingphenylcyclobutylmethylamine ether derivatives (7, 8) which were purifiedby silica gel column chromatography using a gradient of hexane and ethylacetate. The pure products (7, 8) gave satisfactory 1H NMR and/or Massspectral data. The selected racemic ether derivatives (7, 8) weresubjected to chiral HPLC to get the corresponding optically pure (R)-and (S)-isomers. The chiral HPLC conditions: column—CHIRAL PAK IA4.6×250 mm, 5 μM; mobile phase—0.1% DEA in hexane and ethanol; isocraticmethod with 0.8 ml per minute flow rate; injection volume 1.00 ul; andrun time 20 min. All ether derivatives (7, 8) were converted in to thecorresponding HCl salts by treating them with 1N HCl dioxane/waterfollowed by lyophilization. The hydrochloride salts of ether derivatives(7, 8) were tested in monoamine transporters (MATs) in vitropharmacology assays.

Example 141-(1-(4-Ethoxyphenyl)cyclobutyl)-N-(2-methoxyethyl)-3-methylbutan-1-amine(7a)

Colorless oil (100 mg, 28% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.66(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.08-1.12 (m,1H); 1.41 (t, J=9.2 Hz, 3H); 1.59-1.68 (m, 1H); 1.71-1.89 (m, 2H);2.16-2.38 (m, 4H); 2.73 (dbroad, J=3.2 Hz, 1H); 2.88 (t, J=6.8 Hz, 2H);3.32 (s, 3H); 3.45 (t, J=7.2 Hz, 2H); 4.03 (q, J=7.2 Hz, 2H); 6.83 (d,J=8.4 Hz, 2H); 7.16 (d, J=8.4 Hz, 2H). MS (ESI): m/z=320.61 (M+H⁺).

Example 15N-(2-Ethoxyethyl)-1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutan-1-amine(7b)

Colorless oil (70 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.66(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.08-1.12 (m,1H); 1.21 (t, J=9.6 Hz, 3H); 1.38-1.44 (m, 4H); 1.59-1.66 (m, 1H);1.75-1.86 (m, 2H); 2.15-2.18 (m, 1H); 2.28-2.37 (m, 3H); 2.73 (dbroad,J=11.6 Hz, 1H); 2.73-2.92 (m, 2H); 3.43-3.50 (m, 3H); 4.03 (q, J=7.2 Hz,2H); 6.83 (d, J=8.4 Hz, 2H); 7.16 (d, J=8.4 Hz, 2H). MS (ESI):m/z=334.72 (M+H⁺).

Example 161-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methyl-N-(2-propoxyethyl)butan-1-amine(7c)

Colorless oil (80 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.66(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.91-0.92 (m,6H); 1.00-1.08 (m, 1H); 1.39-1.46 (m, 4H); 1.52-1.64 (m, 3H); 1.73-1.86(m, 2H); 2.17-2.40 (m, 4H); 2.73 (sbroad, 1H); 2.88-2.94 (m, 2H); 3.36(t, J=6.8 Hz, 2H); 3.48 (d, J=10.8 Hz, 2H); 4.03 (q, J=7.2 Hz, 2H); 6.83(d, J=8.4 Hz, 7.16 (d, J=8.4 Hz, 1H). MS (ESI): m/z=348.40 (M+H⁺).

Example 17N-(2-Butoxyethyl)-1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutan-1-amine(7d)

Colorless oil (100 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.66(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.92 (t, J=9.6Hz, 3H); 1.08-1.12 (m, 1H); 1.32-1.44 (m, 5H); 1.49-1.64 (m, 3H);1.78-1.86 (m, 1H); 2.04-2.15 (m, 1H); 2.26-2.39 (m, 2H); 2.73 (dbroad,J=11.6 Hz, 1H); 2.86-2.91 (m, 2H); 3.38-3.48 (m, 4H); 3.64 (t, J=7.2H,1H); 4.03 (q, J=7.2 Hz, 2H); 4.277 (t, J=6.8 Hz, 1H); 6.82 (d, J=8.4 Hz,2H); 7.15 (d, J=8.4 Hz, 2H). MS (ESI): m/z=362.57 (M+H⁺).

Example 181-(1-(4-Ethoxyphenyl)cyclobutyl)-N-(2-isobutoxyethyl)-3-methylbutan-1-amine(7e)

Colorless oil (90 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.66(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.90-1.04 (m,6H); 1.08-1.12 (m, 1H); 1.38-1.44 (m, 4H); 1.60-1.68 (m, 1H); 1.70-1.91(m, 3H); 2.13-2.20 (m, 1H); 2.27-2.42 (m, 3H); 2.71 (d, J=8.4 Hz, 1H);2.85-2.92 (m, 2H); 3.17 (d, J=6.4 Hz, 2H); 3.58 (t, J=7.2H, 1H); 4.03(q, J=7.2 Hz, 2H); 6.82 (d, J=8.4 Hz, 2H); 7.15 (d, J=8.4 Hz, 2H). MS(ESI): m/z=362.57 (M+H⁺).

Example 19N-(2-Ethoxyethyl)-3-methyl-1-(1-(4-(methylthio)phenyl)cyclobutyl)butan-1-amine(7f)

Colorless oil (0.20 g, 20%). ¹HNMR (400 MHz, CDCl₃): δ 0.60-0.66 (m,1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 1.06-1.09 (m, 1H);1.17 (t, J=7.2 Hz, 3H); 1.61-1.60 (m, 1H); 1.70-1.77 (m, 1H); 1.82-1.88(1H); 2.14-2.19 (m, 3H); 2.23-2.29 (m, 2H); 2.35-2.41 (m, 1H); 2.46 (s,3H); 2.72 (d, J=10 Hz, 1H); 2.88 (t, J=7.2H, 2H); 3.42-3.48 (m, 3H);7.02 (d, J=8.8 Hz, 2H); 7.20 (d, J=8.8 Hz, 2H). MS (ESI): m/z=336.20(M+H⁺).

Example 20N-(4-Ethoxybutyl)-3-methyl-1-(1-(4-(methylthio)phenyl)cyclobutyl)butan-1-amine(7g)

Colorless oil (0.21 g, 20%). ¹HNMR (400 MHz, CDCl₃): δ 0.60-0.66 (m,1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 1.87 (t, J=7.2 Hz,3H); 1.47-1.83 (m, 6H); 2.04-2.22 (m, 3H); 2.27-2.32 (m, 2H); 2.46 (s,3H); 3.40-3.49 (m, 5H); 4.10-4.15 (m, 4H); 7.02 (d, J=8.8 Hz, 2H); 7.20(d, J=8.8 Hz, 2H). MS (ESI): m/z=364.20 (M+H⁺).

Example 211-(1-(4-Chlorophenyl)cyclobutyl)-N-(2-ethoxyethyl)-3-methylbutan-1-amine(7h)

¹HNMR (400 MHz, CDCl₃): δ 0.63-0.71 (m, 1H); 0.81 (d, J=6.8 Hz, 3H);0.86 (d, J=6.8 Hz, 3H); 1.01-1.07 (m, 1H); 1.17 (t, J=7.2 Hz, 3H);1.59-1.66 (m, 1H); 1.70-1.77 (m, 1H); 1.83-1.90 (m, 1H); 2.12-2.17 (m,1H); 2.22-2.29 (m, 2H); 2.36-2.43 (m, 1H); 2.73 (dd, J=2.4 Hz; 10.0 Hz,1H); 2.88 (t, J=5.6 Hz, 2H); 3.43-3.48 (m, 4H); 7.16 (d J=8.4 Hz, 2H);7.23 (d, J=8.4 Hz, 2H). MS (ESI): m/z=325.10 (M+H⁺).

Example 22N-(2-Ethoxyethyl)-1-(1-(4-fluorophenyl)cyclobutyl)-3-methylbutan-1-amine(7i)

¹HNMR (400 MHz, CDCl₃): δ 0.64-0.71 (m, 1H); 0.82 (d, J=6.8 Hz, 3H);0.86 (d, J=6.8 Hz, 3H); 1.02-1.08 (m, 1H); 1.17 (t, J=7.2 Hz, 3H);1.59-1.66 (m, 1H); 1.70-1.78 (m, 1H); 1.83-1.92 (m, 1H); 2.12-2.17 (m,2H); 2.21-2.31 (m, 2H); 2.36-2.43 (m, 1H); 2.72 (dd, J=2.4 Hz; 10.0 Hz,1H); 2.88 (t, J=5.6 Hz, 2H); 3.43-3.44 (m, 4H); 6.95 (t, J=8.8 Hz, 2H);7.18 (dd, J=5.2 Hz; 8.8 Hz, 2H). MS (ESI): m/z=308.67 (M+H⁺).

Example 23N-(2-Ethoxyethyl)-3-methyl-1-(1-(p-tolyl)cyclopropyl)butan-1-amine (7j)

Colorless oil (0.24 g, 22%). ¹HNMR (400 MHz, CDCl₃): δ 0.46-0.50 (m,1H); 0.67-0.72 (m, 1H); 0.75-0.79 (m, 1H); 0.80 (d, J=6.8 Hz, 3H); 0.83(d, J=6.8 Hz, 3H); 1.04-1.13 (m, 1H); 1.16-1.20 (m, 4H); 1.23-1.31 (m,1H); 1.70-1.76 (m, 1H); 1.94-1.98 (m, 1H); 2.30 (s, 3H); 2.75-2.80 (m,1H); 3.21-3.27 (m, 1H); 3.45-3.54 (m, 4H); 7.06 (d, J=7.2 Hz, 2H); 7.20(d, J=7.2 Hz, 2H). MS (ESI): m/z=290.20 (M+H⁺).

Example 241-(1-(4-Chlorophenyl)cyclopropyl)-N-(2-ethoxyethyl)-3-methylbutan-1-amine(7k)

Colorless oil (0.22 g, 24%). ¹HNMR (400 MHz, CDCl₃): δ 0.47-0.52 (m,1H); 0.65-0.71 (m, 1H); 0.75-0.89 (m, 7H); 1.02-1.09 (m, 1H); 1.18 (t,J=7.2 Hz, 3H); 1.19-1.27 (m, 1H); 1.44 (sbroad, 2H); 1.68-1.73 (m, 1H);1.95-1.98 (m, 1H); 2.73-2.79 (m, 1H); 3.17-3.23 (m, 1H); 3.47-3.53 (m,2H); 7.06 (d, J=7.2 Hz, 2H); 7.17 (d, J=7.2 Hz, 2H). MS (ESI):m/z=310.20 (M+H⁺).

Example 25N-(2-Ethoxyethyl)-3-methyl-1-(1-(p-tolyl)cyclopentyl)butan-1-amine (7l)

Colorless oil (0.27 g, 22%). ¹HNMR (400 MHz, CDCl₃): δ 0.60-0.75 (m,1H); 0.75 (d, J=6.8 Hz, 3H); 0.78 (d, J=6.8 Hz, 3H); 1.06-1.21 (m, 1H);1.18 (t, J=7.2 Hz, 3H); 1.26-1.47 (m, 3H); 1.57-1.65 (m, 3H); 1.72-1.80(m, 1H); 1.84-2.00 (m, 3H); 2.34 (s, 3H); 2.54 (d, J=8.4 Hz, 1H);2.78-2.85 (m, 1H); 2.86-2.90 (m, 1H); 3.15-3.49 (m, 4H); 6.81 (d, J=8.8Hz, 2H); 7.26 (d, J=8.8 Hz, 2H). MS (ESI): m/z=317.20 (M+H⁺).

Example 26N-(2-Ethoxyethyl)-1-(1-(4-methoxyphenyl)cyclopentyl)-3-methylbutan-1-amine(7m)

Colorless oil (0.27 g, 22%). ¹HNMR (400 MHz, CDCl₃): δ 0.60-0.75 (m,1H); 0.75 (d, J=6.8 Hz, 3H); 0.78 (d, J=6.8 Hz, 3H); 1.06-1.21 (m, 1H);1.18 (t, J=7.2 Hz, 3H); 1.26-1.47 (m, 3H); 1.57-1.65 (m, 3H); 1.72-1.80(m, 1H); 1.84-2.00 (m, 3H); 2.51 (d, J=8.4 Hz, 1H); 2.78-2.85 (m, 1H);2.86-2.90 (m, 1H); 3.15-3.45 (m, 4H); 3.77 (s, 3H); 6.81 (d, J=8.8 Hz,2H); 7.26 (d, J=8.8 Hz, 2H). MS (ESI): m/z=334.20 (M+H⁺).

Example 27N-(4-ethoxybutyl)-3-methyl-1-(1-(p-tolyl)cyclohexyl)butan-1-amine (7n)

Colorless oil (0.18 g, 20%). ¹HNMR (400 MHz, CDCl₃): δ 0.67-0.72 (m,1H); 0.75 (d, J=6.8 Hz, 3H); 0.78 (d, J=6.8 Hz, 3H); 1.13-1.26 (m, 8H);1.36-1.44 (m, 3H); 1.49-1.59 (m, 7H); 2.16 (d, J=12.8 Hz, 1H); 2.21-2.35(m, 5H); 2.44-2.50 (m, 1H); 2.65-2.69 (m, 1H); 3.34-3.48 (m, 4H); 7.23(d, J=8.8 Hz, 2H); 7.28 (d, J=8.8 Hz, 2H). MS (ESI): m/z=360.20 (M+H⁺).

Example 281-(1-(4-Chlorophenyl)cyclohexyl)-N-(4-ethoxybutyl)-3-methylbutan-1-amine(7o)

Colorless oil (0.18 g, 20%). ¹HNMR (400 MHz, CDCl₃): δ 0.58-0.65 (m,1H); 0.75 (d, J=6.8 Hz, 3H); 0.78 (d, J=6.8 Hz, 3H); 1.07-1.13 (m, 1H);1.56-1.26 (m, 6H); 1.38-1.63 (m, 10H); 2.13 (d, J=14.0 Hz, 1H); 2.21 (d,J=10 Hz, 1H); 2.28 (d, J=13.6 Hz, 1H); 2.45-2.51 (m, 1H); 2.68-2.74 (m,1H); 3.36-3.48 (m, 4H); 7.23 (d, J=8.8 Hz, 2H); 7.28 (d, J=8.8 Hz, 2H).MS (ESI): m/z=381.20 (M+H⁺).

Example 291-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(2-ethoxyethyl)-3-methylbutan-1-amine(8a)

Colorless oil (87 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.61-0.68(m, 1H); 0.84 (d, J=6.8 Hz, 3H); 0.89 (d, J=6.8 Hz, 3H); 1.03-1.04 (m,1H); 1.08 (t, J=7.2 Hz, 3H); 1.62-1.63 (m, 1H); 1.75-1.78 (m, 1H);1.88-1.91 (m, 1H); 2.21-2.38 (m, 4H); 2.75 (dd, J=2.4 Hz; 10.0 Hz, 1H);2.96-3.02 (m, 2H); 3.41 (q, J=7.2 Hz, 2H); 3.44 (t, J=4.4 Hz, 2H); 7.06(dd, J=2.4 Hz; 8.4 Hz, 1H); 7.31 (d, J=2.0 Hz, 1H); 7.34 (d, J=8.4 Hz,1H). MS (ESI): m/z=360.10 (M+H⁺).

Example 30(R)-1-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(2-methoxyethyl)-3-methylbutan-1-amine(8b)

Colorless oil (60 mg, 28% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.64-0.71(m, 1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.04 (t, J=12Hz, 1H); 1.53 (sbroad, 1H); 1.62-1.65 (m, 1H); 1.73-1.81 (m, 1H);1.88-1.91 (m, 1H); 2.15-2.25 (m, 3H); 2.37-2.44 (m, 1H); 2.74 (d, J=8.4Hz, 1H); 2.75-2.94 (m, 2H); 2.96 (s, 3H). 3.44 (t, J=10.8 Hz, 2H); 7.06(d, J=8.0 Hz, 1H); 7.33 (s, 1H); 7.34 (d, J=8.0 Hz, 1H). MS (ESI):m/z=346.03 (M+H⁺).

Example 31(S)-1-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(2-methoxyethyl)-3-methylbutan-1-amine(8c)

Colorless oil (100 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.64-0.71(m, 1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.04 (t, J=12Hz, 1H); 1.53 (sbroad, 1H); 1.62-1.65 (m, 1H); 1.73-1.81 (m, 1H);1.88-1.91 (m, 1H); 2.15-2.25 (m, 3H); 2.37-2.44 (m, 1H); 2.74 (d, J=8.4Hz, 1H); 2.75-2.94 (m, 2H); 2.96 (s, 3H). 3.44 (t, J=10.8 Hz, 2H); 7.06(d, J=8.0 Hz, 1H); 7.33 (s, 1H); 7.34 (d, J=8.0 Hz, 1H). MS (ESI):m/z=346.03 (M+H⁺).

Example 32(R)-1-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(3-propoxypropyl)-3-methylbutan-1-amine(8d)

Colorless oil (87 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.66(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.91 (t, J=9.6Hz, 3H); 1.00-1.08 (m, 1H); 1.56-1.64 (m, 5H); 1.66-1.80 (m, 2H);1.83-1.96 (m, 1H); 2.09-2.30 (m, 3H); 2.37-2.46 (m, 1H); 2.72-2.94 (m,3H); 3.37 (t, J=10.8 Hz, 2H); 3.49 (t, J=10.8 Hz, 2H); 7.07 (dd, J=3.2Hz, 11.2 Hz, 1H); 7.32 (s, 1H); 7.33 (d, J=8.4 Hz, 1H). MS (ESI):m/z=388.30 (M+H⁺).

Example 33(S)-1-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(3-propoxypropyl)-3-methylbutan-1-amine(8e)

Colorless oil (60 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.66(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.91 (t, J=9.6Hz, 3H); 1.00-1.08 (m, 1H); 1.56-1.64 (m, 5H); 1.66-1.80 (m, 2H);1.83-1.96 (m, 1H); 2.09-2.30 (m, 3H); 2.37-2.46 (m, 1H); 2.72-2.94 (m,3H); 3.37 (t, J=10.8 Hz, 2H); 3.49 (t, J=10.8 Hz, 2H); 7.07 (dd, J=3.2Hz, 11.2 Hz, 1H); 7.32 (s, 1H); 7.33 (d, J=8.4 Hz, 1H). MS (ESI):m/z=388.30 (M+H⁺).

Example 34(R)—N-(3-Butoxypropyl)-1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutan-1-amine(8f)

Colorless oil (130 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.59-0.64(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.91 (t, J=9.6Hz, 3H); 1.04-1.07 (m, 1H); 1.32-1.40 (m, 2H); 1.50-1.56 (m, 3H);1.57-1.79 (m, 4H); 1.87-1.92 (m, 1H); 2.10-2.27 (m, 3H); 2.38-2.42 (m,1H); 2.72-2.94 (m, 3H); 3.37 (t, J=10.8 Hz, 2H); 3.49 (t, J=10.8 Hz,2H); 7.07 (dd, J=2.0 Hz, 8.0 Hz, 1H); 7.32 (s, 1H); 7.33 (d, J=8.0 Hz,1H). MS (ESI): m/z=402.03 (M+H⁺).

Example 35(S)—N-(3-Butoxypropyl)-1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutan-1-amine(8g)

Colorless oil (130 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.59-0.64(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.91 (t, J=9.6Hz, 3H); 1.04-1.07 (m, 1H); 1.32-1.40 (m, 2H); 1.50-1.56 (m, 3H);1.57-1.79 (m, 4H); 1.87-1.92 (m, 1H); 2.10-2.27 (m, 3H); 2.38-2.42 (m,1H); 2.72-2.94 (m, 3H); 3.37 (t, J=10.8 Hz, 2H); 3.49 (t, J=10.8 Hz,2H); 7.07 (dd, J=2.0 Hz, 8.0 Hz, 1H); 7.32 (s, 1H); 7.33 (d, J=8.0 Hz,1H). MS (ESI): m/z=402.03 (M+H⁺).

Example 36(R)-1-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(4-methoxybutyl)-3-methylbutan-1-amine(8h)

Colorless oil (60 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.66(m, 1H); 0.84 (d, J=8.8 Hz, 3H); 0.89 (d, J=8.8 Hz, 3H); 1.00-1.08 (m,1H); 1.43-1.68 (m, 6H); 1.71-1.94 (m, 2H); 2.10-2.45 (m, 4H); 2.66-2.84(m, 3H); 3.31 (s, 3H). 3.37 (t, J=10.8 Hz, 2H); 7.07 (dd, J=3.2 Hz, 11.6Hz, 1H); 7.32 (s, 1H); 7.34 (d, J=11.6 Hz, 1H). MS (ESI): m/z=374.26(M+H⁺).

Example 37(S)-1-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(4-methoxybutyl)-3-methylbutan-1-amine(8i)

Colorless oil (60 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.66(m, 1H); 0.84 (d, J=8.8 Hz, 3H); 0.89 (d, J=8.8 Hz, 3H); 1.00-1.08 (m,1H); 1.43-1.68 (m, 6H); 1.71-1.94 (m, 2H); 2.10-2.45 (m, 4H); 2.66-2.84(m, 3H); 3.31 (s, 3H). 3.37 (t, J=10.8 Hz, 2H); 7.07 (dd, J=3.2 Hz, 11.6Hz, 1H); 7.32 (s, 1H); 7.34 (d, J=11.6 Hz, 1H). MS (ESI): m/z=374.26(M+H⁺).

Example 38(R)-1-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(4-ethoxybutyl)-3-methylbutan-1-amine(8j)

Colorless oil (100 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.66(m, 1H); 0.84 (d, J=9.2 Hz, 3H); 0.89 (d, J=9.2 Hz, 3H); 1.01-1.08 (m,1H); 1.20 (t, J=9.2 Hz, 3H); 1.43-1.64 (m, 6H); 1.71-1.94 (m, 2H);2.09-2.41 (m, 4H); 2.66-2.84 (m, 3H); 3.40-3.51 (m, 4H). 7.08 (dd, J=2.8Hz, 10.8 Hz, 1H); 7.32 (s, 1H); 7.34 (d, J=10.8 Hz, 1H). MS (ESI):m/z=388.26 (M+H⁺).

Example 39(S)-1-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(4-ethoxybutyl)-3-methylbutan-1-amine(8k)

Colorless oil (100 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.66(m, 1H); 0.84 (d, J=9.2 Hz, 3H); 0.89 (d, J=9.2 Hz, 3H); 1.01-1.08 (m,1H); 1.20 (t, J=9.2 Hz, 3H); 1.43-1.64 (m, 6H); 1.71-1.94 (m, 2H);2.09-2.41 (m, 4H); 2.66-2.84 (m, 3H); 3.40-3.51 (m, 4H). 7.08 (dd, J=2.8Hz, 10.8 Hz, 1H); 7.32 (s, 1H); 7.34 (d, J=10.8 Hz, 1H). MS (ESI):m/z=388.26 (M+H⁺).

Example 401-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(4-isobutoxybutyl)-3-methylbutan-1-amine(8l)

Colorless oil (87 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.59-0.64(m, 1H); 0.84 (d, J=9.2 Hz, 3H); 0.89 (d, J=9.2 Hz, 3H); 0.91 (sbroad,6H); 1.01-1.07 (m, 1H); 1.45-1.63 (m, 6H); 1.66-1.92 (m, 3H); 2.10-2.31(m, 2H); 2.37-2.49 (m, 2H); 2.68-2.82 (m, 3H); 3.16 (d, J=6.4 Hz, 2H);3.40 (t, J=6.4H, 2H); 7.08 (dd, J=2.8 Hz, 10.8 Hz, 1H); 7.32 (s, 1H);7.33 (d, J=10.8 Hz, 1H). MS (ESI): m/z=416.26 (M+H⁺).

Example 411-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(2-ethoxyethyl)propan-1-amine(8n)

¹HNMR (400 MHz, CDCl₃): δ 0.69-0.74 (m, 1H); 0.89 (d, J=6.8 Hz, 3H);1.19 (t, J=6.8 Hz, 3H); 1.39-1.47 (m, 1H); 1.71-1.78 (m, 1H); 1.86-1.96(m, 1H); 2.17-2.27 (m, 3H); 2.36-2.43 (m, 1H); 2.54 (dd, J=2.4 Hz; 10.0Hz, 1H); 2.79-2.85 (m, 1H); 2.88-2.94 (m, 1H); 3.43-3.49 (m, 4H); 7.06(dd, J=2.4 Hz; 8.4 Hz, 1H); 7.30 (s, 1H); 7.32 (d, J=8.4 Hz, 1H). MS(ESI): m/z=332.60 (M+H⁺).

Example 421-(1-(3,4-Dimethoxyphenyl)cyclobutyl)-N-(2-methoxyethyl)-3-methylbutan-1-amine(8o)

Colorless oil (100 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.72-0.78(m, 1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.06-1.12 (m,1H); 1.60-1.68 (m, 1H); 1.77-1.91 (m, 2H); 2.13-2.20 (m, 1H); 2.28-2.40(m, 3H); 2.72 (dbroad, J=9.2 Hz, 1H); 2.89 (t, J=5.6 Hz, 2H); 3.32 (s,3H); 3.45 (t, J=7.2 Hz, 2H); 3.87 (s, 6H); 6.77-6.82 (m, 3H). MS (ESI):m/z=336.70 (M+H⁺).

Example 431-(1-(3,4-Dimethoxyphenyl)cyclobutyl)-N-(2-ethoxyethyl)-3-methylbutan-1-amine(8p)

Colorless oil (88 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.72-0.78(m, 1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.06-1.12 (m,1H); 1.18 (t, J=6.8 Hz, 3H); 1.52 (sbroad, 1H); 1.62-1.67 (m, 1H);1.77-1.89 (m, 2H); 2.15-2.18 (m, 1H); 2.29-2.32 (m, 2H); 2.36-2.40 (m,1H); 2.72 (dd, J=3.2 Hz; 6.8 Hz, 1H); 2.88 (t, J=1.6 Hz, 2H); 3.45-3.49(m, 3H); 3.87 (s, 6H); 6.77-6.82 (m, 3H). MS (ESI): m/z=350.80 (M+H⁺).

Example 441-(1-(3,4-Dimethoxyphenyl)cyclobutyl)-N-(3-methoxypropyl)-3-methylbutan-1-amine(8q)

Colorless oil (80 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.70-0.74(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.06-1.12 (m,1H); 1.63-1.72 (m, 3H); 1.76-1.88 (m, 2H); 2.13-2.16 (m, 1H); 2.27-2.32(m, 2H); 2.37-2.40 (m, 1H); 2.71 (dd, J=2.4 Hz; 9.6 Hz, 1H); 2.80-2.84(m, 2H); 3.32 (s, 3H); 3.45 (t, J=6.4 Hz, 2H); 3.87 (s, 6H); 6.76-6.82(m, 3H). MS (ESI): m/z=350.80 (M+H⁺).

Example 451-(1-(3,4-Dimethoxyphenyl)cyclobutyl)-N-(3-ethoxypropyl)-3-methylbutan-1-amine(8r)

Colorless oil (100 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.70-0.74(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.08-1.12 (m,1H); 1.19 (t, J=6.8 Hz, 3H); 1.63-1.72 (m, 3H); 1.76-1.88 (m, 2H);2.13-2.16 (m, 1H); 2.27-2.32 (m, 2H); 2.37-2.40 (m, 1H); 2.71 (dd, J=2.4Hz; 9.6 Hz, 1H); 2.82 (t, J=6.4 Hz, 2H); 3.43-3.50 (m, 4H); 3.87 (s,6H); 6.76-6.82 (m, 3H). MS (ESI): m/z=364.62 (M+H⁺).

Example 461-(1-(3,4-Dimethoxyphenyl)cyclobutyl)-N-(4-methoxybutyl)-3-methylbutan-1-amine(8s)

Colorless oil (130 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.70-0.74(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.08-1.12 (m,1H); 1.57-1.64 (m, 6H); 1.78-1.89 (m, 3H); 2.13-2.16 (m, 1H); 2.27-2.32(m, 2H); 2.37-2.40 (m, 1H); 2.74 (sbroad, 1H); 3.27 (sbroad, 3H); 3.36(t, J=5.6 Hz, 2H); 3.87 (s, 6H); 6.76-6.82 (m, 3H). MS (ESI): m/z=364.62(M+H⁺).

Example 471-(1-(3,4-dimethoxyphenyl)cyclobutyl)-N-(4-ethoxybutyl)-3-methylbutan-1-amine(8t)

Colorless oil (100 mg, 27% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.69-0.74(m, 1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.04-1.12 (m,1H); 1.19 (t, J=6.8 Hz, 3H); 1.24-1.30 (m, 3H); 1.45-1.51 (m, 2H);1.58-1.65 (m, 2H); 2.14-2.18 (m, 1H); 2.27-2.40 (m, 3H); 2.69-2.78 (m,3H); 3.39-3.42 (m, 4H); 3.87 (s, 6H); 6.76-6.82 (m, 3H). MS (ESI):m/z=378.20 (M+H⁺).

General Procedure for Synthesis of Phenylcyclobutylmethylamine ThioetherDerivatives 12 and 13 (Scheme 3)

To a stirred solution of phenylcycloalkylmethylamine (6) (1 eq),alkylthioalkylcarboxylic acid (14) (1.2 eq) and DMAP (0.6 g, 1 eq) in 20mL of DCM at 0° C. under nitrogen atmosphere was added dropwise asolution of dicyclohexylcarbodiimide (DCC) (1.4 g., 0.0070 mol. 1.2 eq)in 10 mL of DCM. After the addition was completed, the reaction mixturewas stirred at room temperature for 15 h. The progress of the reactionwas monitored by thin layer chromatography (TLC). The reaction mixturewas filtered and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography to give thecorresponding amides (15) as white color solid in 70-90% yield. To asuspension of lithium aluminum hydride (LAH) (0.417 g, 4.2 eq) in 20 mLof THF anhydrous was added a solution of amide (15) (1 eq) in 20 mL ofTHF dropwise at 0° C. under nitrogen atmosphere. After the addition wascomplete, the reaction mixture was brought to rt and then to reflux for24 h. The progress of the reaction was monitored by thin layerchromatography (TLC). The reaction mixture was cooled to 0° C. andquenched by adding 2.5 mL of water, followed by 4.5 mL 10% NaOH andfinally 2 mL of water. After stirring for a while, ether was added. Themass was filtered through celite, washed with ethyl acetate. Thecombined filtrates was evaporated and the residue was purified by silicagel chromatography using a gradient of hexane and ethyl acetate aseluents to get the corresponding pure thioether derivatives (12, 13).The pure thioethers (12, 13) gave satisfactory 1H NMR and/or Massspectral data. The selected racemic ether derivatives (12, 13) weresubjected to chiral HPLC to get the corresponding optically pure (R)-and (S)-isomers using similar conditions described for ether derivatives(7,8) in scheme 2. All thioether derivatives (12, 13) were converted into the corresponding HCl salts by treating them with 1N HCldioxane/water followed by lyophilization. The hydrochloride salts ofthioether derivatives (12, 13) were tested in monoamine transporters(MATs) in vitro pharmacology assays.

Example 48N-(4-(Ethylthio)butyl)-1-(1-(4-fluorophenyl)cyclobutyl)-3-methylbutan-1-amine(12a)

Colorless oil (0.47 g, 51% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.63(m, 1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 1.03-1.06 (m,1H); 1.26 (t, J=7.2 Hz, 3H); 1.47-1.54 (m, 2H); 1.56-1.67 (m, 3H);1.71-1.77 (m, 1H); 1.84-1.92 (m, 1H); 2.10-2.17 (m, 1H); 2.20-2.26 (m,2H); 2.34-2.38 (m, 1H); 2.50-2.55 (m, 3H); 2.65-2.72 (m, 2H); 2.74-2.80(m, 2H); 6.97 (dd, J=8.4 Hz; 11.6 Hz, 1H); 7.06 (dd, J=1.6 Hz; 7.6 Hz,1H); 7.12-7.17 (m, 2H). MS (ESI): m/z=352.20 (M+H⁺).

Example 491-(1-(4-Chlorophenyl)cyclobutyl)-N-(4-(ethylthio)butyl)-3-methylbutan-1-amine(12b)

Colorless oil (0.48 g, 51% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.60-0.66(m, 1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 1.03-1.09 (m,3H); 1.25 (t, J=7.2 Hz, 3H); 1.47-1.54 (m, 2H); 1.58-1.65 (m, 2H);1.73-1.78 (m, 1H); 1.84-1.91 (m, 1H); 2.11-2.18 (m, 1H); 2.21-2.29 (m,2H); 2.35-2.42 (m, 1H); 2.50-2.55 (m, 4H); 2.67-2.77 (m, 3H); 7.16 (d,J=8.8 Hz, 2H); 7.25 (d, J=8.8 Hz, 2H). MS (ESI): m/z=369.20 (M+H⁺).

Example 501-(1-(4-Ethoxyphenyl)cyclobutyl)-N-(2-(ethylthio)ethyl)-3-methylbutan-1-amine(12c)

Colorless oil (0.37 g, 52% yield)¹HNMR (400 MHz, CDCl₃): δ 0.69-0.75 (m,1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 1.05-1.11 (m, 1H);1.26 (t, J=7.2 Hz, 3H); 1.40 (t J=7.2 Hz, 3H); 1.54-1.66 (m, 2H);1.72-1.74 (m, 1H); 1.82-1.88 (m, 1H); 2.03-2.18 (m, 1H); 2.25-2.36 (m,2H); 2.52 (q, J=7.6 Hz, 2H); 2.61 (t, J=6.8 Hz, 2H); 2.70 (dd, J=2.0 Hz;9.6 Hz, 1H); 2.90 (t, J=6.8 Hz, 2H); 4.01 (q, J=7.2 Hz, 2H); 6.82 (d,J=8.4 Hz, 2H); 7.15 (d, J=8.4 Hz, 2H). MS (ESI): m/z=350.20 (M+H⁺).

Example 514-(Butylthio)-N-(1-(1-(4-ethoxyphenyl)cyclobutyl)propyl)butan-1-amine(12d)

Colorless oil (0.47 g, 53% yield)¹HNMR (400 MHz, CDCl₃): δ 0.72-0.80 (m,1H); 0.84-0.91 (m, 6H); 1.34-1.46 (m, 6H); 1.48-1.65 (m, 6H); 1.71-1.80(m, 1H); 1.82-1.89 (m, 1H); 2.15-2.37 (m, 4H); 2.46-2.51 (m, 5H);2.63-2.75 (m, 2H); 4.01 (q, J=7.2 Hz, 2H); 6.82 (d, J=8.4 Hz, 2H); 7.15(d, J=8.4 Hz, 2H). MS (ESI): m/z=378.20 (M+H⁺).

Example 521-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(2-(ethylthio)ethyl)-3-methylbutan-1-amine(13a)

Colorless oil (0.41 g, 53% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.60-0.67(m, 1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 1.03-1.06 (m,2H); 1.26 (t, J=7.2 Hz, 3H); 1.55-1.61 (m, 1H); 1.70-1.74 (m, 1H);1.80-1.86 (m, 1H); 2.08-2.14 (m, 1H); 2.18-2.23 (m, 2H); 2.30-2.35 (m,1H); 2.43-2.50 (m, 2H); 2.53-2.60 (m, 2H); 2.68 (d, J=10.0 Hz, 1H);2.81-2.91 (m, 2H); 7.04 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.30 (d, J=2.0H,1H); 7.32 (d, J=8.4 Hz, 1H). MS (ESI): m/z=376.20 (M+H⁺).

Example 53N-(2-(Butylthio)ethyl)-1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutan-1-amine(13b)

Colorless oil (0.27 g, 50% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.60-0.67(m, 1H); 0.81-0.92 (m, 9H); 1.04-1.10 (m, 1H); 1.34-1.45 (m, 2H);1.50-1.58 (m, 2H); 1.60-1.65 (m, 1H); 1.73-1.78 (m, 1H); 1.85-1.91 (m,1H); 2.15-2.19 (m, 1H); 2.23-2.30 (m, 2H); 2.35-2.40 (m, 1H); 2.46-2.50(m, 2H); 2.58-2.62 (m, 2H); 2.68 (dd, J=2.4 Hz; 10.0 Hz, 1H); 2.85-2.93(m, 2H); 7.04 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.30 (d, J=2.0H, 1H); 7.32 (d,J=8.4 Hz, 1H). MS (ESI): m/z=403.20 (M+H⁺).

Example 541-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(4-(ethylthio)butyl)-3-methylbutan-1-amine(13c)

Colorless oil (0.37 g, 52% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.63(m, 1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 1.03-1.06 (m,1H); 1.26 (t, J=7.2 Hz, 3H); 1.47-1.54 (m, 2H); 1.56-1.67 (m, 3H);1.71-1.77 (m, 1H); 1.84-1.92 (m, 1H); 2.10-2.17 (m, 1H); 2.20-2.26 (m,2H); 2.34-2.38 (m, 1H); 2.50-2.55 (m, 3H); 2.65-2.72 (m, 2H); 2.74-2.80(m, 2H); 7.04 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.30 (d, J=2.0H, 1H); 7.32 (d,J=8.4 Hz, 1H). MS (ESI): m/z=403.20 (M+H⁺).

Example 55N-(4-(Butylthio)butyl)-1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutan-1-amine(13d)

Colorless oil (0.45 g, 55% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.63(m, 1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 0.88 (t, J=7.2Hz, 3H); 1.02-1.05 (m, 1H); 1.36-1.43 (m, 2H); 1.48-1.65 (m, 7H);1.73-1.77 (m, 1H); 1.85-1.90 (m, 1H); 2.10-2.16 (m, 1H); 2.18-2.25 (m,2H); 2.34-2.39 (m, 1H); 2.48-2.52 (m, 4H); 2.65-2.80 (m, 3H); 7.04 (dd,J=2.0 Hz; 8.4 Hz, 1H); 7.30 (d, J=2.0H, 1H); 7.32 (d, J=8.4 Hz, 1H). MS(ESI): m/z=431.20 (M+H⁺).

Example 561-(1-(2,4-Dichlorophenyl)cyclobutyl)-N-(4-(ethylthio)butyl)-3-methylbutan-1-amine(13e)

Colorless oil (0.57 g, 51% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.63(m, 1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 1.03-1.06 (m,1H); 1.26 (t, J=7.2 Hz, 3H); 1.47-1.54 (m, 2H); 1.56-1.67 (m, 3H);1.71-1.77 (m, 1H); 1.84-1.92 (m, 1H); 2.10-2.17 (m, 1H); 2.20-2.26 (m,2H); 2.34-2.38 (m, 1H); 2.50-2.55 (m, 3H); 2.65-2.72 (m, 2H); 2.74-2.80(m, 2H); 7.02 (d, J=8.4 Hz, 1H); 7.16 (dd, J=2 Hz; 8.4 Hz, 1H); 7.29 (d,J=2.4 Hz, 1H). MS (ESI): m/z=403.20 (M+H⁺).

Example 571-(1-(3,4-dichlorophenyl)cyclobutyl)-N-(2-(ethylthio)ethyl)propan-1-amine(13f)

Colorless oil (0.27 g, 52% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.72-0.79(m, 1H); 0.92 (t, J=7.6 Hz, 3H); 1.23 (t, J=7.6 Hz, 3H); 1.42-1.48 (m,1H); 1.72-1.79 (m, 1H); 1.86-1.93 (m, 1H); 2.18-2.30 (m, 3H); 2.34-2.41(m, 1H); 2.49-2.55 (m, 3H); 2.60-2.69 (m, 2H); 2.80-2.89 (m, 1H);2.86-2.97 (m, 1H); 7.04 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.30 (d, J=2.0H,1H); 7.32 (d, J=8.4 Hz, 1H). MS (ESI): m/z=347.20 (M+H⁺).

Example 584-(Butylthio)-N-(1-(1-(3,4-dichlorophenyl)cyclobutyl)propyl)butan-1-amine(13g)

Colorless oil (0.37 g, 50% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.69-0.83(m, 1H); 0.84-0.91 (m, 6H); 1.03-1.05 (m, 1H); 1.34-1.41 (m, 4H);1.51-1.65 (m, 6H); 1.72-1.77 (m, 1H); 1.85-1.92 (m, 1H); 2.17-2.30 (m,2H); 2.34-2.41 (m, 1H); 2.45-2.50 (m, 4H); 2.62-2.68 (m, 1H); 2.72-2.78(m, 1H); 7.04 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.30 (d, J=2.0H, 1H); 7.32 (d,J=8.4 Hz, 1H). MS (ESI): m/z=403.20 (M+H⁺).

General Procedure for Synthesis of PhenylcyclobutylmethylamineAlkylsulfonyl Derivatives 17 (Scheme 4)

Synthesis of Amide Derivatives (16, Step 1):

To a stirred solution of m-CPBA (m-chloroperbenzoic acid) (0.94 g, 2.1eq) in 10 mL of THF was added at −30° C. (dry Ice/acetone) drop wiseover 30 minutes a solution of amide (15) (0.0026 mol) in 10 mL of THF.The reaction progress was monitored by TLC. After the reaction wascompleted, 3 mL of triethylamine (TEA) was added followed by a solutionof 10 mL saturated sodium bicarbonate. The organic layer was separated,washed with brine, dried over Na₂SO₄ and evaporated. The residue waspurified by silica gel chromatography using a gradient of hexane andethyl acetate as eluents to get the corresponding pure amides (16).

Synthesis of Alkylsulfonyl Derivatives (17, Step 2):

To a suspension of Lithium aluminum hydride (LAH) (0.3 g, 4.2 eq) in 20mL of THF anhydrous was added amide (16) (1 eq) in 10 mL of THF dropwiseat 0° C. under nitrogen atmosphere. After the addition was complete, thereaction mixture was brought to room temperature and then to reflux for15 h. The progress of the reaction was monitored by thin layerchromatography (TLC). The reaction mixture was cooled to 0° C. andquenched by adding 5 mL of water, followed by 9 mL 10% NaOH and finally4 mL of water. After stirring for a while, ether was added. The mass wasfiltered through celite and washed with ethyl acetate. The combinedfiltrates were evaporated and the residue was purified by silica gelcolumn chromatography using a gradient of hexane and ethyl acetate toget the corresponding sulfonyl derivatives (17). The pure sulfonylderivatives (17) gave satisfactory 1H NMR and/or Mass spectral data. Allsulfonyl derivatives (17) were converted in to the corresponding HClsalts by treating them with 1N HCl dioxane/water followed bylyophilization. The hydrochloride salts of alkylsulfonyl derivatives(17) were tested in monoamine transporters (MATs) in vitro pharmacologyassays.

Example 59N-(1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)-4-(ethylsulfonyl)butanamide(16a)

Colorless oil (0.85 g, 73% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.71(m, 1H); 0.80 (d, J=6.8 Hz, 3H); 0.90 (d, J=6.8 Hz, 3H); 1.13-1.19 (m,1H); 1.24 (t, J=7.2 Hz, 3H); 1.78-1.84 (m, 1H); 2.05-2.23 (m, 5H);2.25-2.32 (m, 2H); 2.37-2.47 (m, 2H); 2.96-3.07 (m, 4H); 4.47-4.53 (m,1H); 4.93 (d, J=10.4 Hz, 1H); 6.94 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.16 (d,J=2.0H, 1H); 7.38 (d, J=8.4 Hz, 1H). MS (ESI): m/z=449.20 (M+H⁺).

Example 604-(butylsulfonyl)-N-(1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)butanamide(16b)

Colorless oil (0.85 g, 73% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.71(m, 1H); 0.80 (d, J=6.8 Hz, 3H); 0.91 (t, J=7.2 Hz, 3H); 0.95 (d, J=6.8Hz, 3H); 1.13-1.19 (m, 1H); 1.38-1.50 (m, 3H) 1.75-1.85 (m, 3H);2.05-2.23 (m, 5H); 2.25-2.32 (m, 2H); 2.37-2.47 (m, 2H); 2.93-2.97 (m,2H); 3.01-3.05 (m, 2H); 4.47-4.53 (m, 1H); 4.93 (d, J=10.4 Hz, 1H); 6.94(dd, J=2.0 Hz; 8.4 Hz, 1H); 7.16 (d, J=2.0H, 1H); 7.38 (d, J=8.4 Hz,1H). MS (ESI): m/z=477.20 (M+H⁺).

Example 611-(1-(3,4-Dichlorophenyl)cyclobutyl)-N-(4-(ethylsulfonyl)butyl)-3-methylbutan-1-amine(17a)

Colorless oil (0.11 g, 31% yield)¹HNMR (400 MHz, CDCl₃): δ 0.58-0.65 (m,1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 1.03-1.08 (m, 1H);1.38 (t, J=7.2 Hz, 3H); 1.52-1.59 (m, 3H); 1.74-1.78 (m, 1H); 1.84-1.93(m, 3H); 2.08-2.15 (m, 1H); 2.17-2.28 (m, 2H); 2.31-2.36 (m, 1H);2.66-2.71 (m, 2H); 2.78-2.83 (m, 1H); 2.93-3.00 (m, 4H); 7.04 (dd, J=2.0Hz; 8.4 Hz, 1H); 7.30 (d, J=2.0H, 1H); 7.32 (d, J=8.4 Hz, 1H). MS (ESI):m/z=435.20 (M+H⁺).

Example 62N-(4-(Butylsulfonyl)butyl)-1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutan-1-amine(17b)

Colorless oil (0.07 g, 37% yield)¹HNMR (400 MHz, CDCl₃): δ 0.59-0.65 (m,1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 0.95 (t, J=7.2 Hz,3H); 1.03-1.05 (m, 1H); 1.43-1.51 (m, 2H); 1.52-1.62 (m, 3H); 1.72-1.86(m, 4H); 1.88-1.93 (m, 3H); 2.08-2.38 (m, 4H); 2.66-2.71 (m, 2H);2.78-2.84 (m, 1H); 2.91-2.97 (m, 4H); 7.04 (dd, J=2.0 Hz; 8.4 Hz, 1H);7.30 (d, J=2.0H, 1H); 7.32 (d, J=8.4 Hz, 1H). MS (ESI): m/z=463.20(M+H⁺).

General Procedure for Synthesis of Phenylcycloalkylamine Derivates 19(Scheme 5)

Synthesis of Amides (21, Step 1):

To a stirred solution of trimethylaluminum 2 M solution (4 mL, 0.008mol) in toluene was added dropwise a solution of phenylcycloalkylamine(6) (0.0053 mol, 1 eq) and ester (20) (0.0053 mol, 1 eq) in tolueneunder nitrogen atmosphere at 0° C. in a sealed tube. The reactionmixture was stirred at 80° C. for 5 h. The reaction progress wasmonitored by TLC. After completion of the reaction, the mixture wasconcentrated under vacuum, quenched with crushed ice and extracted withethyl acetate (15 mL×3). The combined extract was dried over sodiumsulfate and concentrated under reduced pressure. The residue was passedthrough a short column to get the pure amide (21). The amides (21a-d)were prepared according to this protocol. The starting esters (20) wereprepared by alkylating the cyclic pyrrolidine and piperidine withappropriate bromoalkylcarboxylic acid esters under standard conditionsusing triethylamine (TEA) as a base in DCM as a solvent in good yields.

The amides (21e-f) were prepared by coupling 4-N,N-dimethylbutanoic acidwith phenylcycloalkylamine (6) using HATU as a coupling agent. To astirred solution of amine (6) (1 eq), 4-N,N-dimethylbutanoic acid (1 eq)and HATU (2 eq) solution in DCM was added dropwise a solution ofN,N-diisopropylethylamine (DIEA) (3 eq) under nitrogen atmosphere at 0°C. The reaction mixture was stirred at room temperature for 5 h. Thereaction progress was monitored by TLC. After completion of thereaction, the mixture was quenched with water and extracted with DCM,the combined extracts was dried over Na₂SO₄, and then evaporated underreduced pressure. The residue was purified by silica gel columnchromatography using a gradient of DCM and methanol as eluents to getthe pure amides (21e-f). The amides (21a-f) gave satisfactory 1H NMR andmass (LC/MS) mass data. As a representative example, the 1H NMR and massdata of amide (21d) is given herein.

Synthesis of Amines (19, Step 2):

Borane-DMS (1.5 eq) in THF was added dropwise to an ice cooled solutionof amide (21) (1 eq) in THF. The reaction mixture was stirred at 60° C.for 3 h. After completion of reaction, reaction mass was quenched withice cooled water and then extracted twice with EtOAc. The combinedorganic layers were washed with brine and dried over Na₂SO₄. The organiclayer was evaporated under reduced pressure. The crude product was inthe form of amine-borane adduct or complex. The free base form of aminederivative (19) was obtained by treating the amine-borane complexaccording to the reported methods using Raney Nickel in methanol(Couturier, M. et al, Organic Letters, 2001, vol 3 (No. 3), 465-467) orpiperazine in methanol (Zhou, Q. et al, Organic letters 2011, vol 13(No. 3), 526-529). The crude free base form of amine derivatives (19)were purified by preparative HPLC using a gradient of hexane and ethanolas eluents to obtain the pure amine derivatives (19).

Example 63N-(1-(1-(3,4-Dimethoxyphenyl)cyclobutyl)-3-methylbutyl)-4-(piperidin-1-yl)butanamide(21d)

Colorless oil (0.85 g, 39% yield); ¹HNMR (300 MHz, DMSOd₆): δ 0.73-0.76(m, 6H); 0.85-0.98 (m, 2H); 1.39-1.59 (m, 8H); 1.71 (b, 3H); 1.83-1.89(m, 2H); 2.11-2.17 (m, 6H); 2.27-2.49 (m, 4H); 3.73 (s, 3H); 3.74 (s,3H); 4.19-4.25 (m, 1H), 6.62 (s, 1H), 6.64 (bs, 1H), 6.89 (d, J=7.8 Hz,1H); 7.30 (bd, 1H, D₂O exchangeable); MS (ESI): m/z=431.17 (M+H⁺).

Example 641-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methyl-N-(4-(pyrrolidin-1-yl)butyl)butan-1-amine(19a)

Colorless oil (0.092 g, 18.7% yield); ¹HNMR (300 MHz, DMSOd₆): δ0.61-0.67 (m, 1H); 0.85 (d, J=7.2 Hz, 3H); 0.90 (d, J=6.4 Hz, 3H);1.04-1.10 (m, 1H); 1.36-1.43 (m, 3H); 1.56-1.62 (m, 2H); 1.67-1.78 (m,2H); 1.80-1.90 (m, 4H); 1.95-2.30 (m, 4H); 2.67-2.84 (m, 7H); 3.21 (bt,2H); 7.07 (dd, J=2 Hz, 8 Hz, 1H), 7.31 (d, J=2 Hz, 1H); 7.34 (d, J=8.4Hz, 1H); MS (ESI): m/z=411.16 (M+).

Example 651-(1-(3,4-Dimethoxyphenyl)cyclobutyl)-3-methyl-N-(4-(pyrrolidin-1-yl)butyl)butan-1-amine(19b)

Colorless oil (0.085 g, 17.7% yield). ¹HNMR (300 MHz, CDCl₃): δ0.69-0.75 (m, 1H); 0.84 (d, J=6.6 Hz, 3H); 0.88 (d, J=6.6 Hz, 3H);1.07-1.14 (m, 1H); 1.35-1.48 (m, 5H); 1.80-1.86 (m, 6H); 2.14-2.17 (m,2H); 2.30-2.35 (m, 2H); 2.67-2.77 (m, 7H); 3.19 (bt, 2H); 3.87 (s, 6H);6.79-6.81 (m, 3H); MS (ESI): m/z=403.23 (M+H⁺).

Example 661-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methyl-N-(4-(piperidin-1-yl)butyl)butan-1-amine(19c)

Colorless oil (0.015 g, 15.6% yield); ¹HNMR (300 MHz, DMSOd₆): δ0.59-0.62 (m, 1H); 0.79 (d, J=6.6 Hz, 3H); 0.84 (d, J=6.6 Hz, 3H);0.94-1.02 (m, 1H); 1.33-1.38 (m, 2H); 1.46-1.48 (m, 3H); 1.59-1.75 (m,8H); 2.11-2.16 (m, 2H); 2.43-2.50 (m, 2H); 2.65-2.77 (m, 9H); 7.20 (dd,J=5.1 Hz; 8.4 Hz, 1H); 7.42 (d, J=1.8 Hz, 1H); 7.51 (d, J=8.1 Hz, 1H).MS (ESI): m/z=425.13 (M+).

Example 671-(1-(3,4-Dimethoxyphenyl)cyclobutyl)-3-methyl-N-(4-(piperidin-1-yl)butyl)butan-1-amine(19d)

Colorless oil (0.060 g, 15.5% yield). ¹HNMR (400 MHz, CDCl₃): δ0.61-0.67 (m, 1H); 0.85 (d, J=6.8 Hz, 3H); 0.97 (d, J=6.8 Hz, 3H);1.07-1.14 (m, 1H); 1.22-1.28 (m, 2H); 1.33-1.47 (m, 3H); 1.58-1.71 (m,2H); 1.61-1.67 (m, 2H); 1.73-2.30 (m, 6H); 2.35-2.42 (m, 1H); 2.67-2.84(m, 8H); 3.23 (sbroad, 2H); 3.87 (s, 6H); 6.79-6.81 (m, 3H). MS (ESI):m/z=417.20 (M+H⁺).

Example 68N1-(1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)-N⁴,N⁴-dimethylbutane-1,4-diamine(19e)

Colorless oil (0.045 g, 11.6% yield). ¹HNMR (400 MHz, CDCl₃): δ0.59-0.65 (m, 1H); 0.80 (d, J=6.8 Hz, 3H); 0.84 (d, J=6.8 Hz, 3H);0.95-1.02 (m, 1H); 1.22-1.28 (m, 1H); 1.33-1.47 (m, 3H); 1.59-1.71 (m,4H); 1.81-1.87 (m, 2H); 1.73-2.30 (m, 3H); 2.35-2.42 (m, 2H); 2.36-2.58(m, 6H); 2.60-2.74 (m, 2H); 7.06 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.31 (d,J=2.0H, 1H); 7.35 (d, J=8.4 Hz, 1H). MS (ESI): m/z=386.20 (M+H⁺).

Example 69N1-(1-(1-(3,4-dimethoxyphenyl)cyclobutyl)-3-methylbutyl)-N⁴,N⁴-dimethylbutane-1,4-diamine(19f)

Colorless oil (0.08 g, 20% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.59-0.65(m, 1H); 0.80 (d, J=6.8 Hz, 3H); 0.84 (d, J=6.8 Hz, 3H); 0.95-1.02 (m,1H); 1.22-1.28 (m, 1H); 1.33-1.47 (m, 3H); 1.59-1.71 (m, 4H); 1.81-1.87(m, 2H); 1.73-2.30 (m, 3H); 2.35-2.42 (m, 2H); 2.36-2.58 (m, 6H);2.60-2.74 (m, 2H); 3.87 (s, 6H); 6.79-6.81 (m, 3H). MS (ESI): m/z=377.20(M+H⁺).

General Procedure for Synthesis of Alkoxyalkyl 4-Nitrobenzenesulfonates9 (Scheme 6)

Synthesis of Monobenzyloxy Carbinols (24, Step 1):

To a stirred suspension of NaH (3.5 g, 1.04 eq) in dry THF (50 mL) wasadded diol (23) (3 eq) over 0.5 h at 0° C. After the addition wascomplete, the mixture was brought to reflux and benzyl bromide (10 mL,0.084 mol., 1 eq) was added dropwise. The reaction mixture was stirredat reflux for 12 h. The progress of the reaction was monitored by thinlayer chromatography (TLC). After the reaction was complete, the mixturewas allowed to cool to room temperature, and diluted with ether. Thecombined extracts were dried over MgSO₄, filtered, and concentratedunder reduced pressure. The residue was passed through a short silicagel column using a gradient of hexane and ethyl acetate as eluents toget the pure monobenzyloxycarbinol (24) as a colorless oil in moderateyields.

Synthesis of Alkoxyalkylbenzyl Ethers (25, Step 2):

To a stirred suspension of NaH (0.75 g, 1.5 eq) in dry DMF (20 mL) wasadded monobenzyloxycarbinol (24) (1 eq) in 10 mL of DMF at 0° C. Afterthe addition was complete, the mixture was stirred for 1 h and thenadded dropwise a solution of appropriate alkyl bromide or iodide (2 eq).The reaction mixture was stirred for 15 h and the progress of thereaction was monitored by thin layer chromatography (TLC). Aftercompletion of the reaction, the mixture was diluted with 25 mL water,extracted with ethyl acetate, dried over anhydrous MgSO₄, filtered, andconcentrated under reduced pressure. The resulting oil was purified bysilica gel column chromatography using a gradient of hexane and ethylacetate as eluents to get the corresponding alkoxyalkyl benzyl ethers(25) as colorless oil.

Alkoxyalkylsulfonates (9, Step 3):

To a stirred suspension of Pd/C (10%)(activated)(0.8 g) in ethanol (10mL) was added solution of alkoxyalkyl benzyl ether (25) (0.001 mol) in10 mL of ethanol. The reaction mixture was kept under hydrogen pressurefor 15 h. The progress of the reaction was monitored by thin layerchromatography (TLC). After the reaction was complete, the mixture wasfiltered through Celite, washed with ethyl acetate and the filtratesolution was concentrated under reduced pressure. The residue was passedthrough a short silica gel column using a gradient of hexane and diethylether as eluents to get the corresponding carbinolether (26) ascolorless oil. The carbinolether (26) was treated with 4-nitrosulfonylchloride in presence a mild base triethylamine (TEA) in DCM at 0° C. to5° C. The progress of the reaction was monitored by TLC. After thereaction was complete, the mixture was washed with water, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography using a gradient ofhexane and ethyl acetate as eluents to get the alkoxyalkylsulfonates(9).

Example 70 2-Ethoxyethyl 4-nitrobenzenesulfonate (9a)

White solid (1.87 g, 93% yield). ¹HNMR (400 MHz, CDCl₃): δ 1.08 (t,J=7.2 Hz, 3H); 3.41 (q, J=7.2 Hz, 2H); 3.61 (t, J=4.4 Hz, 2H); 4.28 (t,J=4.4 Hz, 2H); 8.16 (d, J=8.8 Hz, 2H); 8.37 (d, J=8.8 Hz, 2H).

Example 71 2-Methoxyethyl 4-nitrobenzenesulfonate (9b)

White solid (1.87 g, 93% yield). ¹HNMR (400 MHz, CDCl₃): δ 3.28 (s, 3H);3.59 (t, J=4.4 Hz, 2H); 4.30 (t, J=4.4 Hz, 2H); 8.13 (d, J=8.8 Hz, 2H);8.40 (d, J=8.8 Hz, 2H).

Example 72 2-Ethoxybutyl 4-nitrobenzenesulfonate (9c)

White solid (1.87 g, 93% yield). ¹HNMR (400 MHz, CDCl₃): δ 1.08 (t,J=6.8 Hz, 3H); 1.59-1.63 (m, 2H); 1.76-1.83 (m, 2H); 3.37-3.45 (m, 4H);4.19 (t, J=6.4 Hz, 2H); 8.11 (d, J=8.8 Hz, 2H); 8.40 (d, J=8.8 Hz, 2H).

Example 73 2-Methoxybutyl 4-nitrobenzenesulfonate (9d)

White solid (1.87 g, 93% yield). ¹HNMR (400 MHz, CDCl₃): δ 1.57-1.63 (m,2H); 1.72-1.82 (m, 2H); 3.28 (s, 3H); 3.33-3.44 (m, 3H); 4.10 (t, J=6.4Hz, 2H); 8.11 (d, J=8.8 Hz, 2H); 8.40 (d, J=8.8 Hz, 2H).

Example 74 4-Propoxybutyl 4-nitrobenzenesulfonate (9e)

White solid (1.87 g, 93% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.84 (t,J=7.2 Hz, 3H); 1.44-1.51 (m, 2H); 1.91-1.97 (m, 2H); 3.28 (t, J=6.8 Hz,2H); 3.43 (t, J=, 5.6 Hz, 2H); 4.26 (t, J=6.4 Hz, 2H); 8.11 (d, J=8.8Hz, 2H); 8.40 (d, J=8.8 Hz, 2H).

Example 75 4-Butoxypropyl 4-nitrobenzenesulfonate (9f)

White solid (1.87 g, 93% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.88 (t,J=7.2 Hz, 3H); 1.25-1.31 (m, 2H); 1.41-1.47 (m, 2H); 1.94 (t, J=6.0 Hz,2H); 3.31 (t, J=6.4 Hz, 2H); 3.42 (t, J=, 5.6 Hz, 2H); 4.26 (t, J=6.4Hz, 2H); 8.11 (d, J=8.8 Hz, 2H); 8.40 (d, J=8.8 Hz, 2H).

Example 76 Ethyl 4-ethoxybutanoate (30) (Scheme 7)

Sulfuric acid 0.25 mL (0.0045 mmol, 0.035 eq) was added to an ice cooledsolution of γ-butyrolactone (28) (11.2 g, 0.13009 mmol, 1.0 eq),triethyl orthoformate (29) (41.1 mL, 0.2497 mmol., 1.92 eq) in 100 mL ofethanol. The mixture was heated at 50° C. for 12 h while monitoring thereaction by TLC. The reaction mixture was cooled to room temperature andmost of the solvent was evaporated under reduced pressure. Theconcentrated reaction mixture was quenched with cold saturated NaHCO₃solution and extracted with ethyl acetate twice. The combined organicextracts was dried over anhydrous Na₂SO₄ and concentrated under vacuumto yielded 20 g (95%) of ethyl 4-ethoxybutanoate (30) as light yellowoil. ¹HNMR (400 MHz, CDCl₃): δ 1.16-1.28 (m, 6H); 1.87-1.91 (m, 2H);2.39 (t, J=9.6 Hz; 2H); 3.42-3.50 (m, 2H); 3.57-3.64 (m, 2H); 4.13 (q,J=6 Hz, 2H).

Example 77 4-Ethoxybutanoic acid (10) (Scheme 7)

To an ice cold stirred solution of ethyl 4-ethoxybutanoate (30) (˜1 g)in 10 mL of tetrahydrofuran (THF) was added aqueous NaOH solution (0.62g in 7 ml of H₂O) and stirred at room temperature for 12 h, whilemonitoring the reaction by TLC. Most of the solvent was evaporated underreduced pressure and the residue was diluted with water (10 mL). Theaqueous layer was acidified with 1N HCl solution (PH˜2) and thenextracted with ethyl acetate (15 mL×3). The combined organic extractswas dried over anhydrous Na₂SO₄ and concentrated under vacuum to yield0.6 g (73.14) of 4-ethoxybutanoic acid as light yellow oil. ¹HNMR (400MHz, CDCl₃): δ 1.20 (t, J=9.2 Hz, 3H); 1.87-1.95 (m, 2H); 2.47 (t, J=10Hz; 2H); 3.48 (q, J=9.2 Hz, 4H).

General Procedure for Synthesis of Alkylthioalkylcarboxylic Acid Esters(33) (Scheme 8)

To a stirred solution of sodium alkanethiolate (32) (1 eq) in anhydrousDMF (10 mL) at 0° C. was added bromoalkylcarboxylic acid ester (31) (1eq) over 5 min. The reaction mixture was stirred for 15 h at roomtemperature. The progress of the reaction was monitored by thin layerchromatography (TLC). The reaction mixture was diluted with ethylacetate (20 mL) and washed with saturated NaHCO₃ solution (the aqueouslayer was quenched with bleach). The organic layer was dried overanhydrous Na₂SO₄ to give the corresponding alkylthioethercarboxylic acidester (33) which was purified by silica gel column chromatography usinga gradient of hexane and ethyl acetate and isolated as colorless oil

Example 78 Ethyl 4-(ethylthio)butanoate (33a)

Colorless oil (6.87 g, 100% yield). ¹HNMR (400 MHz, CDCl₃): δ 1.20-1.26(m, 6H); 1.84-1.92 (m, 2H); 2.40 (t, J=9.6 Hz, 2H); 2.47-2.55 (m, 4H);4.12 (q, J=7.2 Hz, 2H).

Example 79 Ethyl 2-(ethylthio)acetate (33b)

Colorless oil (5.87 g, 90% yield). ¹HNMR (400 MHz, CDCl₃): δ 1.20-1.29(m, 6H); 2.63 (q, J=7.6 Hz, 2H); 3.19 (s, 2H); 4.15 (q, J=7.2 Hz, 2H).

Example 80 Ethyl 4-(butylthio)butanoate (33c)

Colorless oil (14.12 g, 100% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.89 (t,J=7.6 Hz, 3H); 1.22 (t, J=7.6 Hz, 3H); 1.34-1.36 (m, 2H); 1.48-1.54 (m,2H); 1.87-1.90 (m, 2H); 2.39 (t, J=7.6 Hz, 2H); 2.44-2.51 (m, 4H); 4.10(q, J=7.6 Hz, 2H)

Example 81 Ethyl 2-(butylthio)acetate (33d)

Colorless oil (5.80 g, 100% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.89 (t,J=6.8 Hz, 3H); 1.26 (t, J=7.2 Hz, 3H); 1.36-1.41 (m, 2H); 1.52-1.61 (m,2H); 2.61 (t, J=7.6 Hz, 2H); 3.18 (s, 2H); 4.15 (q, J=7.2 Hz, 2H)

General Procedure for Synthesis of Alkylthioether Carboxylic Acids (14)(Scheme 8)

To a stirred solution of alkylthioethercarboxylic acid ester (33) (0.1mole, 1 eq) in ethanol (20 mL) was added 2N aq. NaOH (1.5 eq) dropwiseinto the reaction mixture. The reaction mixture was stirred roomtemperature for 30 min (the reaction progress is monitored by TLC).After the reaction was completed, the reaction mixture was concentratedon a rotavapor and the residue was cooled in ice bath. A few pieces ofcrushed ice were introduced into the flask and neutralized with 1N HCl.The product was extracted with ethyl acetate (20×20 mL). The combinedextracts was dried over Na₂SO₄ and evaporated at 0° C. on rotavap. Theresidue was purified by silica gel column chromatography using hexane aseluents to get the pure alkylthioether carboxylic acids (14).

Example 82 4-(Ethylthio)butanoic acid (14a)

Colorless oil (2.01 g, 90% yield). ¹HNMR (400 MHz, CDCl₃): δ 1.26 (t,J=7.6 Hz, 3H); 1.84-1.92 (m, 2H); 2.40 (t, J=9.6 Hz, 2H); 2.47-2.55 (m,4H); 10.92 (sbroad, 1H).

Example 83 2-(Butylthio)acetic acid (14b)

Colorless oil (0.77 g, 77% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.89 (t,J=7.6 Hz, 3H); 1.37-1.43 (m, 2H); 1.54-1.60 (m, 2H); 2.65 (t, J=7.6 Hz,2H); 3.23 (s, 2H); 10.00 (sbroad, 1H).

Example 84 2-(Ethylthio)acetic acid (14c)

Colorless oil (4.76 g, 85% yield). ¹HNMR (400 MHz, CDCl₃): δ 1.26 (t,J=7.6 Hz, 3H); 2.65 (q, J=7.6 Hz, 2H); 3.22 (s, 2H); 10.92 (sbroad, 1H).

Example 85 4-(Butylthio)butanoic acid (14d)

Colorless oil (3.64 g, 80% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.89 (t,J=7.6 Hz, 3H); 1.35-1.41 (m, 2H); 1.50-1.56 (m, 2H); 1.88-1.93 (m, 2H);2.47-2.50 (m, 4H); 2.55 (t, J=7.2 Hz, 2H); 10.89 (sbroad, 1H).

Example 86

In Vitro Pharmacology Results

The monoamine transporters inhibitory activities of selectedcycloalkylmethylamines of Formula (I) are reported herein. The compoundswere evaluated using well established radioligand binding assaysprotocols (Galli, A. et al., J. Exp. Biol. 1995, 198, 2197-2212; Giros,B. et al., Trends Pharmcol. Sci. 1993, 14, 43-49; Gu, H. et al., J.Biol. Chem. 1994, 269(10), 7124-7130; Shearman, L. P. et al, Am. J.Physiol., 1998, 275(6 Pt 1), C1621-1629; Wolf, W. A. et al., J. Biol.Chem. 1992, 267(29), 20820-20825). The human recombinant transporterproteins dopamine (DAT), norepinephrine (NET) and serotonin (SERT) wereselected for the in vitro assays. The radioligand binding assays werecarried out at 11 different test concentrations 0.1 nM to 1 μM.

The assays were carried out in duplicates and the quantitative data arereported as Ki in the Table 1.

DAT NET SERT Example Compound Ki (nM) Ki (nM) Ki (nM) 20  7g 92.02 37.212.99 29  8a 2.38 46.72 1.40 32  8d 5.45 72.05 3.80 36  8h 2.39 12.691.19 38  8j 1.16 11.01 0.80 49 12b 67.56 51.87 18.77 50 12c 115.70 14223.31 54 13c 23.93 17.07 14.84 55 13d 104.20 51.03 65.33 57 13f 49.19 119224 61 17a 29.45 44.72 38.40

What is claimed is:
 1. A compound of structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: n is 1; SP is aspacer of C₁₋₆ alkylene; X is NR⁶; R¹ and R² are independently H, C₁₋₆alkoxy, or halogen; R³ is H or C₁₋₆ alkyl; R⁴ is H; R⁵ is C₁₋₆ alkyl; R⁶is H or C₁₋₆ alkyl; optionally R¹-R⁶ are independently substituted with²H (deuterium); and “*” denotes a carbon capable of being opticallyactive.
 2. The compound according to claim 1, wherein R¹ and R² areindependently C₁₋₆ alkoxy or halogen.
 3. The compound according to claim1, wherein R³ is isobutyl.
 4. The compound according to claim 1, whereinR¹ is H and R² is halogen or alkoxy.
 5. The compound according to claim1, wherein R⁵ is ethyl.
 6. The compound according to claim 1, which isat least about in 95% enantiomeric excess in R-form over S-form.
 7. Thecompound according to claim 6, which is an optical pure R-form.
 8. Thecompound according to claim 1, which is at least about in 95%enantiomeric excess in S-form over R-form.
 9. The compound according toclaim 8, which is an optical pure S-form.
 10. A pharmaceuticalcomposition comprising the compound of claim 1 and a pharmaceuticallyacceptable vehicle.
 11. A compound having the following structure:

wherein n is 1, SP is butylene, R¹¹ and R¹² are chloro, R¹³ is isobutyl,and R¹⁴ is ethyl.